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Sample records for ctgf factor clave

  1. The Role of Connective Tissue Growth Factor (CTGF/CCN2) in Skeletogenesis

    PubMed Central

    Arnott, John A; Lambi, Alex G; Mundy, Christina M; Hendesi, Honey; Pixley, Robin A; Owen, Thomas A; Safadi, Fayez F; Popoff, Steven N

    2012-01-01

    Connective tissue growth factor (CTGF) is a 38kDa, cysteine rich, extracellular matrix protein composed of four domains or modules. CTGF has been shown to regulate a diverse array of cellular functions and has been implicated in more complex biological processes such as angiogenesis, chondrogenesis, and osteogenesis. A role for CTGF in the development and maintenance of skeletal tissues first came to light in studies demonstrating its expression in cartilage and bone cells which was dramatically increased during skeletal repair or regeneration. The physiological significance of CTGF in skeletogenesis was confirmed in CTGF-null mice, which exhibited multiple skeletal dysmorphisms as a result of impaired growth plate chondrogenesis, angiogenesis, and bone formation/mineralization. Given the emerging importance of CTGF in osteogenesis and chondrogenesis, this review will focus on its expression in skeletal tissues, its effects on osteoblast and chondrocyte differentiation and function, and the skeletal implications of ablation or over-expression of CTGF in knockout or transgenic mouse models, respectively. In addition, this review will examine the role of integrin-mediated signaling and the regulation of CTGF expression as it relates to skeletogenesis. We will emphasize CTGF studies in bone or bone cells, and will identify opportunities for future investigations concerning CTGF and chondrogenesis/osteogenesis. PMID:21967332

  2. Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis

    PubMed Central

    Jiang, Jie; Leong, Natalie L.; Khalique, Umara.; Phan, Tien M.; Lyons, Karen M.; Luck, James V.

    2016-01-01

    Introduction Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. Aim We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. Methods Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. Results All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin-and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. Conclusion Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products. PMID:27704689

  3. Alteration of Connective Tissue Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy.

    PubMed

    Tsai, Chieh-Chih; Wu, Shi-Bei; Chang, Pei-Chen; Wei, Yau-Huei

    2015-01-01

    Graves' ophthalmopathy (GO) is a disfiguring and sometimes blinding disease, which is characterized by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. The aim of this study is to investigate whether the expression levels of fibrosis-related genes, especially that of connective tissue growth factor (CTGF), are altered in orbital fibroblasts of patients with GO. The role of oxidative stress in the regulation of CTGF expression in GO orbital fibroblasts is also examined. By a SYBR Green-based real time quantitative PCR (RT-QPCR), we demonstrated that the mRNA expression levels of fibronectin, apolipoprotein J, and CTGF in cultured orbital fibroblasts from patients with GO were significantly higher than those of age-matched normal controls (p = 0.007, 0.037, and 0.002, respectively). In addition, the protein expression levels of fibronectin, apolipoprotein J, and CTGF analyzed by Western blot were also significantly higher in GO orbital fibroblasts (p = 0.046, 0.032, and 0.008, respectively) as compared with the control. Furthermore, after treatment of orbital fibroblasts with a sub-lethal dose of hydrogen peroxide (200 μM H2O2), we found that the H2O2-induced increase of CTGF expression was more pronounced in the GO orbital fibroblasts as compared with those in normal controls (20% vs. 7%, p = 0.007). Importantly, pre-incubation with antioxidants including N-acetylcysteine (NAC) and vitamin C, respectively, resulted in significant attenuation of the induction of CTGF in GO orbital fibroblasts in response to H2O2 (p = 0.004 and 0.015, respectively). Taken together, we suggest that oxidative stress plays a role in the alteration of the expression of CTGF in GO orbital fibroblasts that may contribute to the pathogenesis and progression of GO. Antioxidants may be used in combination with the therapeutic agents for effective treatment of GO.

  4. Alteration of Connective Tissue Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with Graves’ Ophthalmopathy

    PubMed Central

    Chang, Pei-Chen; Wei, Yau-Huei

    2015-01-01

    Graves’ ophthalmopathy (GO) is a disfiguring and sometimes blinding disease, which is characterized by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. The aim of this study is to investigate whether the expression levels of fibrosis-related genes, especially that of connective tissue growth factor (CTGF), are altered in orbital fibroblasts of patients with GO. The role of oxidative stress in the regulation of CTGF expression in GO orbital fibroblasts is also examined. By a SYBR Green-based real time quantitative PCR (RT-QPCR), we demonstrated that the mRNA expression levels of fibronectin, apolipoprotein J, and CTGF in cultured orbital fibroblasts from patients with GO were significantly higher than those of age-matched normal controls (p = 0.007, 0.037, and 0.002, respectively). In addition, the protein expression levels of fibronectin, apolipoprotein J, and CTGF analyzed by Western blot were also significantly higher in GO orbital fibroblasts (p = 0.046, 0.032, and 0.008, respectively) as compared with the control. Furthermore, after treatment of orbital fibroblasts with a sub-lethal dose of hydrogen peroxide (200 μM H2O2), we found that the H2O2-induced increase of CTGF expression was more pronounced in the GO orbital fibroblasts as compared with those in normal controls (20% vs. 7%, p = 0.007). Importantly, pre-incubation with antioxidants including N-acetylcysteine (NAC) and vitamin C, respectively, resulted in significant attenuation of the induction of CTGF in GO orbital fibroblasts in response to H2O2 (p = 0.004 and 0.015, respectively). Taken together, we suggest that oxidative stress plays a role in the alteration of the expression of CTGF in GO orbital fibroblasts that may contribute to the pathogenesis and progression of GO. Antioxidants may be used in combination with the therapeutic agents for effective treatment of GO. PMID:26599235

  5. Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer.

    PubMed

    Wells, Julia E; Howlett, Meegan; Cole, Catherine H; Kees, Ursula R

    2015-08-01

    Connective tissue growth factor (CTGF/CCN2) has long been associated with human cancers. The role it plays in these neoplasms is diverse and tumour specific. Recurring patterns in clinical outcome, histological desmoplasia and mechanisms of action have been found. When CTGF is overexpressed compared to low-expressing normal tissue or is underexpressed compared to high-expressing normal tissue, the functional outcome favours tumour survival and disease progression. CTGF acts by altering proliferation, drug resistance, angiogenesis, adhesion and migration contributing to metastasis. The pattern of CTGF expression and tumour response helps to clarify the role of this matricellular protein across a multitude of human cancers.

  6. Decorin Interacts with Connective Tissue Growth Factor (CTGF)/CCN2 by LRR12 Inhibiting Its Biological Activity*

    PubMed Central

    Vial, Cecilia; Gutiérrez, Jaime; Santander, Cristian; Cabrera, Daniel; Brandan, Enrique

    2011-01-01

    Fibrotic disorders are the end point of many chronic diseases in different tissues, where an accumulation of the extracellular matrix occurs, mainly because of the action of the connective tissue growth factor (CTGF/CCN2). Little is known about how this growth factor activity is regulated. We found that decorin null myoblasts are more sensitive to CTGF than wild type myoblasts, as evaluated by the accumulation of fibronectin or collagen III. Decorin added exogenously negatively regulated CTGF pro-fibrotic activity and the induction of actin stress fibers. Using co-immunoprecipitation and in vitro interaction assays, decorin and CTGF were shown to interact in a saturable manner with a Kd of 4.4 nm. This interaction requires the core protein of decorin. Experiments using the deletion mutant decorin indicated that the leucine-rich repeats (LRR) 10–12 are important for the interaction with CTGF and the negative regulation of the cytokine activity, moreover, a peptide derived from the LRR12 was able to inhibit CTGF-decorin complex formation and CTGF activity. Finally, we showed that CTGF specifically induced the synthesis of decorin, suggesting a mechanism of autoregulation. These results suggest that decorin interacts with CTGF and regulates its biological activity. PMID:21454550

  7. Growth differentiation factor 8 suppresses cell proliferation by up-regulating CTGF expression in human granulosa cells.

    PubMed

    Chang, Hsun-Ming; Pan, Hui-Hui; Cheng, Jung-Chien; Zhu, Yi-Min; Leung, Peter C K

    2016-02-15

    Connective tissue growth factor (CTGF) is a matricellular protein that plays a critical role in the development of ovarian follicles. Growth differentiation factor 8 (GDF8) is mainly, but not exclusively, expressed in the mammalian musculoskeletal system and is a potent negative regulator of skeletal muscle growth. The aim of this study was to investigate the effects of GDF8 and CTGF on the regulation of cell proliferation in human granulosa cells and to examine its underlying molecular determinants. Using dual inhibition approaches (inhibitors and small interfering RNAs), we have demonstrated that GDF8 induces the up-regulation of CTGF expression through the activin receptor-like kinase (ALK)4/5-mediated SMAD2/3-dependent signaling pathways. In addition, the increase in CTGF expression contributes to the GDF8-induced suppressive effect on granulosa cell proliferation. Our findings suggest that GDF8 and CTGF may play critical roles in the regulation of proliferative events in human granulosa cells.

  8. Inhibition of connective tissue growth factor (CTGF/CCN2) in gallbladder cancer cells leads to decreased growth in vitro

    PubMed Central

    Garcia, Patricia; Leal, Pamela; Ili, Carmen; Brebi, Priscilla; Alvarez, Hector; Roa, Juan C

    2013-01-01

    Gallbladder cancer (GBC) is an aggressive neoplasm associated with late diagnosis, unsatisfactory treatment and poor prognosis. Previous work showed that connective tissue growth factor (CTGF) expression is increased in this malignancy. This matricellular protein plays an important role in various cellular processes and its involvement in the tumorigenesis of several human cancers has been demonstrated. However, the precise function of CTGF expression in cancer cells is yet to be determined. The aim of this study was to evaluate the CTGF expression in gallbladder cancer cell lines, and its effect on cell viability, colony formation and in vitro cell migration. CTGF expression was evaluated in seven GBC cell lines by Western blot assay. Endogenous CTGF expression was downregulated by lentiviral shRNA directed against CTGF mRNA in G-415 cells, and the effects on cell viability, anchorage-independent growth and migration was assessed by comparing them to scrambled vector-transfected cells. Knockdown of CTGF resulted in significant reduction in cell viability, colony formation and anchorage-independent growth (P < 0.05). An increased p27 expression was observed in G-415 cells with loss of CTGF function. Our results suggest that high expression of this protein in gallbladder cancer may confer a growth advantage for neoplastic cells. PMID:23593935

  9. Inhibition of connective tissue growth factor (CTGF/CCN2) expression decreases the survival and myogenic differentiation of human rhabdomyosarcoma cells.

    PubMed

    Croci, Stefania; Landuzzi, Lorena; Astolfi, Annalisa; Nicoletti, Giordano; Rosolen, Angelo; Sartori, Francesca; Follo, Matilde Y; Oliver, Noelynn; De Giovanni, Carla; Nanni, Patrizia; Lollini, Pier-Luigi

    2004-03-01

    Connective tissue growth factor (CTGF/CCN2), a cysteine-rich protein of the CCN (Cyr61, CTGF, Nov) family of genes, emerged from a microarray screen of genes expressed by human rhabdomyosarcoma cells. Rhabdomyosarcoma is a soft tissue sarcoma of childhood deriving from skeletal muscle cells. In this study, we investigated the role of CTGF in rhabdomyosarcoma. Human rhabdomyosarcoma cells of the embryonal (RD/12, RD/18, CCA) and the alveolar histotype (RMZ-RC2, SJ-RH4, SJ-RH30), rhabdomyosarcoma tumor specimens, and normal skeletal muscle cells expressed CTGF. To determine the function of CTGF, we treated rhabdomyosarcoma cells with a CTGF antisense oligonucleotide or with a CTGF small interfering RNA (siRNA). Both treatments inhibited rhabdomyosarcoma cell growth, suggesting the existence of a new autocrine loop based on CTGF. CTGF antisense oligonucleotide-mediated growth inhibition was specifically due to a significant increase in apoptosis, whereas cell proliferation was unchanged. CTGF antisense oligonucleotide induced a strong decrease in the level of myogenic differentiation of rhabdomyosarcoma cells, whereas the addition of recombinant CTGF significantly increased the proportion of myosin-positive cells. CTGF emerges as a survival and differentiation factor and could be a new therapeutic target in human rhabdomyosarcoma.

  10. [Connective tissue growth factors, CTGF and Cyr61 in drug-induced gingival overgrowth--an animal model].

    PubMed

    Ciobanică, Mihaela; Cianga, Corina; Căruntu, Irina-Draga; Grigore, Georgiana; Cianga, P

    2008-01-01

    Human gingival overgrowth may occur as a side effect of chronic administration of some therapeutic agents. The mechanisms responsible for the gingival tissues lesions, fibrosis and inflamation, involve an impaired balance between the production and the degradation of type I collagen. It has been demonstrated that CCN2/CTGF, a connective tissue growth factor, is highly expressed in the gingival tissues and positively correlated with the degree of fibrosis in the drug-induced gingival overgrowth. The aim of this study was to identify the presence and localization of CCN2/CTGF and CCN1/Cyr61, members of the same molecular family, in gingival tissues of cyclosporin A- and nifedipine-treated rats, by immunohistochemistry. Staining was evaluated with light microscope and the results show cellular and extracellular CTGF in nifedipin gingival overgrowth tissues with intensity of labeling higher compared to the CsA gingival overgrowth tissues or the controls. The staining for Cyr61 shows its intracellular localization with no diference of labeling intensity between drug-induced gingival overgrowth and normal tissues. Also, we were interested in the gingival TGF-â expression in those animals. We didn't find any commercial anti-rat TGF antibody and our anti-human antibody shows no cross-reactivity with rat tissues. The data from our study sustain the involvement of CTGF and Cyr61 as growth factors in the gingival tissues and the CTGF association with drug-induced gingival overgrowth.

  11. Inverse expression of cystein-rich 61 (Cyr61/CCN1) and connective tissue growth factor (CTGF/CCN2) in borderline tumors and carcinomas of the ovary.

    PubMed

    Bartel, Frank; Balschun, Katharina; Gradhand, Elise; Strauss, Hans G; Dittmer, Jürgen; Hauptmann, Steffen

    2012-09-01

    Members of the CCN [cystein-rich 61 (Cyr61)/connective tissue growth factor (CTGF)/nephroblastoma (NOV)] protein family are involved in the regulation of cellular proliferation, apoptosis, and migration and are also assumed to play a role in carcinogenesis. Therefore, we performed a retrospective study to investigate the immunohistochemical expression of both Cyr61 and CTGF in 92 borderline tumors (BOTs) and 107 invasive carcinomas of the ovary (IOCs). To determine their diagnostic and prognostic value, we correlated protein expression with clinicopathologic factors including overall and disease-free survival. Cyr61 and CTGF were found to be inversely expressed in both BOTs and IOCs, with a stronger expression of Cyr61 in IOCs. Moreover, Cyr61 was found to be preferentially expressed in high-grade serous carcinomas, whereas CTGF was found more frequently in low-grade serous carcinomas. Weak Cyr61 levels correlated with both low estrogen receptor and p53 expression (P=0.038, P=0.04, respectively). However, no association was observed between CTGF, estrogen receptor, and p53 expression levels in IOCs. Regarding prognosis, Cyr61 was found to be of no value, but the loss of CTGF was found to be associated with a poor prognosis in multivariate analysis of overall (relative risk 2.8; P=0.050) and disease-free (relative risk 2.3; P=0.031) survival. Cyr61 and CTGF are inversely expressed in BOTs and IOCs, and loss of CTGF independently indicates poor prognosis in IOCs.

  12. MicroRNA-145 Inhibits Cell Migration and Invasion and Regulates Epithelial-Mesenchymal Transition (EMT) by Targeting Connective Tissue Growth Factor (CTGF) in Esophageal Squamous Cell Carcinoma.

    PubMed

    Han, Qiang; Zhang, Hua-Yong; Zhong, Bei-Long; Wang, Xiao-Jing; Zhang, Bing; Chen, Hua

    2016-10-23

    BACKGROUND This study investigated the mechanism of miR-145 in targeting connective tissue growth factor (CTGF), which affects the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of ESCC cells. MATERIAL AND METHODS A total of 50 ESCC tissues and their corresponding normal adjacent esophageal tissue samples were collected. Then, miR-145 expression in both ESCC clinical specimens and cell lines was detected using quantitative real-time PCR. CTGF protein was detected using immunohistochemistry. Dual luciferase reporter gene assay was employed to assess the effect of miR-145 on the 3'UTR luciferase activity of CTGF. Eca109 cells were transfected with miR-145 mimics and CTGF siRNA, respectively, and changes in cellular proliferation, migration, and invasion were detected via MTT assay, wound-healing assay, and Transwell assay, respectively. Western blotting assay was used to detect the expression of marker genes related to EMT. RESULTS MiR-145 was significantly down-regulated in ESCC tissues and cell lines compared with normal tissues and cell lines (P<0.05). We found significantly more positively expressed CTGF protein in ESCC tissues was than in normal adjacent esophageal tissues (P<0.01). Dual luciferase reporter gene assay showed that miR-145 can specifically bind with the 3'UTR of CTGF and significantly inhibit the luciferase activity by 55% (P<0.01). Up-regulation of miR-145 or down-regulation of CTGF can suppress the proliferation, migration, invasion, and EMT process of ESCC cells. CONCLUSIONS MiR-145 was significantly down-regulated in ESCC tissues and cell lines, while the protein expression of CTGF exhibited the opposite trend. MiR-145 inhibited the proliferation, migration, invasiveness, and the EMT process of ESCC cells through targeted regulation of CTGF expression.

  13. MicroRNA-145 Inhibits Cell Migration and Invasion and Regulates Epithelial-Mesenchymal Transition (EMT) by Targeting Connective Tissue Growth Factor (CTGF) in Esophageal Squamous Cell Carcinoma

    PubMed Central

    Han, Qiang; Zhang, Hua-Yong; Zhong, Bei-Long; Wang, Xiao-Jing; Zhang, Bing; Chen, Hua

    2016-01-01

    Background This study investigated the mechanism of miR-145 in targeting connective tissue growth factor (CTGF), which affects the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of ESCC cells. Material/Methods A total of 50 ESCC tissues and their corresponding normal adjacent esophageal tissue samples were collected. Then, miR-145 expression in both ESCC clinical specimens and cell lines was detected using quantitative real-time PCR. CTGF protein was detected using immunohistochemistry. Dual luciferase reporter gene assay was employed to assess the effect of miR-145 on the 3′UTR luciferase activity of CTGF. Eca109 cells were transfected with miR-145 mimics and CTGF siRNA, respectively, and changes in cellular proliferation, migration, and invasion were detected via MTT assay, wound-healing assay, and Transwell assay, respectively. Western blotting assay was used to detect the expression of marker genes related to EMT. Results MiR-145 was significantly down-regulated in ESCC tissues and cell lines compared with normal tissues and cell lines (P<0.05). We found significantly more positively expressed CTGF protein in ESCC tissues was than in normal adjacent esophageal tissues (P<0.01). Dual luciferase reporter gene assay showed that miR-145 can specifically bind with the 3′UTR of CTGF and significantly inhibit the luciferase activity by 55% (P<0.01). Up-regulation of miR-145 or down-regulation of CTGF can suppress the proliferation, migration, invasion, and EMT process of ESCC cells. Conclusions MiR-145 was significantly down-regulated in ESCC tissues and cell lines, while the protein expression of CTGF exhibited the opposite trend. MiR-145 inhibited the proliferation, migration, invasiveness, and the EMT process of ESCC cells through targeted regulation of CTGF expression. PMID:27771733

  14. Increased expression of connective tissue growth factor (CTGF) in multiple organs after exposure of non-human primates (NHP) to lethal doses of radiation

    PubMed Central

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G.; Gibbs, Allison M.; Smith, Cassandra P.; Taylor-Howell, Cheryl; Kearney, Sean R.; MacVittie, Thomas J.

    2015-01-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP, and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition respectively, suggesting possible crosstalk between spleen and other organs. Our data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs. PMID:26425899

  15. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

    PubMed

    Zhang, Pei; Cui, Wanchang; Hankey, Kim G; Gibbs, Allison M; Smith, Cassandra P; Taylor-Howell, Cheryl; Kearney, Sean R; MacVittie, Thomas J

    2015-11-01

    Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.

  16. CTGF — EDRN Public Portal

    Cancer.gov

    CTGF, a major connective tissue mitoattractant secreted by vascular endothelial cells, promotes proliferation and differentiation of chondrocytes. It mediates heparin- and divalent cation-dependent cell adhesion in many cell types including fibroblasts, myofibroblasts, endothelial and epithelial cells. It enhances fibroblast growth factor-induced DNA synthesis. CTGF is expressed in bone marrow and thymic cells. It is also expressed one of two Wilms tumors tested.

  17. MicroRNA-143-3p inhibits hyperplastic scar formation by targeting connective tissue growth factor CTGF/CCN2 via the Akt/mTOR pathway.

    PubMed

    Mu, Shengzhi; Kang, Bei; Zeng, Weihui; Sun, Yaowen; Yang, Fan

    2016-05-01

    Post-traumatic hypertrophic scar (HS) is a fibrotic disease with excessive extracellular matrix (ECM) production, which is a response to tissue injury by fibroblasts. Although emerging evidence has indicated that miRNA contributes to hypertrophic scarring, the role of miRNA in HS formation remains unclear. In this study, we found that miR-143-3p was markedly downregulated in HS tissues and fibroblasts (HSFs) using qRT-PCR. The expression of connective tissue growth factor (CTGF/CCN2) was upregulated both in HS tissues and HSFs, which is proposed to play a key role in ECM deposition in HS. The protein expression of collagen I (Col I), collagen III (Col III), and α-smooth muscle actin (α-SMA) was obviously inhibited after treatment with miR-143-3p in HSFs. The CCK-8 assay showed that miR-143-3p transfection reduced the proliferation ability of HSFs, and flow cytometry showed that either early or late apoptosis of HSFs was upregulated by miR-143-3p. In addition, the activity of caspase 3 and caspase 9 was increased after miR-143-3p transfection. On the contrary, the miR-143-3p inhibitor was demonstrated to increase cell proliferation and inhibit apoptosis of HSFs. Moreover, miR-143-3p targeted the 3'-UTR of CTGF and caused a significant decrease of CTGF. Western blot demonstrated that Akt/mTOR phosphorylation and the expression of CTGF, Col I, Col III, and α-SMA were inhibited by miR-143-3p, but increased by CTGF overexpression. In conclusion, we found that miR-143-3p inhibits hypertrophic scarring by regulating the proliferation and apoptosis of human HSFs, inhibiting ECM production-associated protein expression by targeting CTGF, and restraining the Akt/mTOR pathway.

  18. Simvastatin inhibits transforming growth factor-β1-induced expression of type I collagen, CTGF, and α-SMA in keloid fibroblasts.

    PubMed

    Mun, Je-Ho; Kim, Young-Mi; Kim, Byung-Soo; Kim, Jae-Ho; Kim, Moon-Bum; Ko, Hyun-Chang

    2014-01-01

    Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor, is used to reduce cholesterol levels. Accumulating evidence has revealed the immunomodulatory and anti-inflammatory effects of simvastatin that prevent cardiovascular diseases. In addition, the beneficial effects of statins on fibrosis of various organs have been reported. However, the functional effect of statins on dermal fibrosis of keloids has not yet been explored. The objective of this study was to determine whether simvastatin could affect dermal fibrosis associated with keloids. We examined the effect of simvastatin on transforming growth factor (TGF)-β1-induced production of type I collagen, connective tissue growth factor (CTGF or CCN2), and α-smooth muscle actin (α-SMA). Keloid fibroblasts were cultured and exposed to different concentrations of simvastatin in the presence of TGF-β1, and the effects of simvastatin on TGF-β1-induced collagen and CTGF production in keloid fibroblasts were determined. The type I collagen, CTGF, and α-SMA expression levels and the Smad2 and Smad3 phosphorylation levels were assessed by Western blotting. The effect of simvastatin on cell viability was evaluated by assessing the colorimetric conversion of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. Simvastatin suppressed TGF-β1-induced type I collagen, CTGF, and α-SMA production in a concentration-dependent manner. The TGF-β1-induced Smad2 and Smad3 phosphorylation levels were abrogated by simvastatin pretreatment. The inhibition of type I collagen, CTGF, and α-SMA expression by simvastatin was reversed by geranylgeranyl pyrophosphate, suggesting that the simvastatin-induced cellular responses were due to inhibition of small GTPase Rho involvement. A RhoA activation assay showed that preincubation with simvastatin significantly blocked TGF-β1-induced RhoA activation. The Rho-associated coiled kinase inhibitor Y27632 abrogated TGF-β1-induced production of type I collagen

  19. Role of CTGF in White Matter Development in Tuberous Sclerosis

    DTIC Science & Technology

    2015-02-01

    hypomyelination in the mouse brain. We show that Tsc-deficient neurons secrete excessive amounts of connective tissue growth factor (CTGF), which blocks...We show that Tsc-deficient neurons secrete excessive amounts of connective tissue growth factor (CTGF), which blocks the maturation of...secrete excessive amounts of connective tissue growth factor (CTGF), which in turn blocks the maturation of oligodendrocytes, and thus myelination

  20. Immunohistochemical Detection of CTGF in the Human Eye.

    PubMed

    van Setten, Gysbert B; Trost, Andrea; Schrödl, Falk; Kaser-Eichberger, Alexandra; Bogner, Barbara; van Setten, Mercedes; Heindl, Ludwig M; Grabner, Günther; Reitsamer, Herbert A

    2016-12-01

    Purpose/Aim of the study: Connective tissue growth factor (CTGF) is a key player in the control of extracellular matrix remodeling, fibrosis, and angiogenesis. It is also involved in the modification of the trabecular meshwork, thus potentially modulating outflow facility and intraocular pressure (IOP). As a consequence, CTGF might be relevant for the development of elevated IOP, a major risk factor in glaucoma-pathogenesis. While comprehensive information on the origins of CTGF in the human eye is not available, the goal of this study is to identify ocular sources of CTGF using morphological methods.

  1. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

    PubMed Central

    Bennewith, Kevin L.; Huang, Xin; Ham, Christine M.; Graves, Edward E.; Erler, Janine T.; Kambham, Neeraja; Feazell, Jonathan; Yang, George P.; Koong, Albert

    2009-01-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted subcutaneously. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by PET imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed co-localization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer. PMID:19179545

  2. Connective Tissue Growth Factor (CTGF) as a Regulator of Lactogenic Differentiation

    DTIC Science & Technology

    2009-06-09

    and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic ...pituitary gland, such as growth hormone (GH), also play roles in ductal morphogenesis during puberty. In ovariectomized mice, treatment with estrogen...restores the TEB formation that had been lost (52), while the treatment with growth hormone rescues the TEB formation in hypophysectomized mice (136

  3. Topically Applied Connective Tissue Growth Factor/CCN2 Improves Diabetic Preclinical Cutaneous Wound Healing: Potential Role for CTGF in Human Diabetic Foot Ulcer Healing

    PubMed Central

    Henshaw, F. R.; Boughton, P.; Lo, L.; McLennan, S. V.; Twigg, S. M.

    2015-01-01

    Aims/Hypothesis. Topical application of CTGF/CCN2 to rodent diabetic and control wounds was examined. In parallel research, correlation of CTGF wound fluid levels with healing rate in human diabetic foot ulcers was undertaken. Methods. Full thickness cutaneous wounds in diabetic and nondiabetic control rats were treated topically with 1 μg rhCTGF or vehicle alone, on 2 consecutive days. Wound healing rate was observed on day 14 and wound sites were examined for breaking strength and granulation tissue. In the human study across 32 subjects, serial CTGF regulation was analyzed longitudinally in postdebridement diabetic wound fluid. Results. CTGF treated diabetic wounds had an accelerated closure rate compared with vehicle treated diabetic wounds. Healed skin withstood more strain before breaking in CTGF treated rat wounds. Granulation tissue from CTGF treatment in diabetic wounds showed collagen IV accumulation compared with nondiabetic animals. Wound α-smooth muscle actin was increased in CTGF treated diabetic wounds compared with untreated diabetic wounds, as was macrophage infiltration. Endogenous wound fluid CTGF protein rate of increase in human diabetic foot ulcers correlated positively with foot ulcer healing rate (r = 0.406; P < 0.001). Conclusions/Interpretation. These data collectively increasingly substantiate a functional role for CTGF in human diabetic foot ulcers. PMID:25789327

  4. Microrna-199a-5p Functions as a Tumor Suppressor via Suppressing Connective Tissue Growth Factor (CTGF) in Follicular Thyroid Carcinoma.

    PubMed

    Sun, Dawei; Han, Shen; Liu, Chao; Zhou, Rui; Sun, Weihai; Zhang, Zhijun; Qu, Jianjun

    2016-04-11

    BACKGROUND The objective of this study was to explore the role of miR-199a-5p in the development of thyroid cancer, including its anti-proliferation effect and downstream signaling pathway. MATERIAL AND METHODS We conducted qRT-PCR analysis to detect the expressions of several microRNAs in 42 follicular thyroid carcinoma patients and 42 controls. We identified CTGF as target of miR-491, and viability and cell cycle status were determined in FTC-133 cells transfected with CTGF siRNA, miR-199a mimics, or inhibitors. RESULTS We identified an underexpression of miR-199a-5p in follicular thyroid carcinoma tissue samples compared with controls. Then we confirmed CTGF as a target of miR-199a-5p thyroid cells by using informatics analysis and luciferase reporter assay. Additionally, we found that mRNA and protein expression levels of CTGF were both clearly higher in malignant tissues than in benign tissues. miR-199a-5p mimics and CTGF siRNA similarly downregulated the expression of CTGF, and reduced the viability of FTC-133 cells by arresting the cell cycle in G0 phase. Transfection of miR-199a-5p inhibitors increased the expression of CTGF and promoted the viability of the cells by increasing the fraction of cells in G2/M and S phases. CONCLUSIONS Our study proves that the CTGF gene is a target of miR-199a-5p, demonstrating the negatively related association between CTGF and miR-199a. These findings suggest that miR-199a-5p might be a novel therapeutic target in the treatment of follicular thyroid carcinoma.

  5. Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2).

    PubMed

    Morales, María Gabriela; Cabrera, Daniel; Céspedes, Carlos; Vio, Carlos P; Vazquez, Yaneisi; Brandan, Enrique; Cabello-Verrugio, Claudio

    2013-07-01

    The renin-angiotensin system (RAS), through angiotensin II and the angiotensin-converting enzyme (ACE), is involved in the genesis and progression of fibrotic diseases characterized by the replacement of normal tissue by an accumulation of an extracellular matrix (ECM). Duchenne muscular dystrophy (DMD) presents fibrosis and a decrease in muscle strength produced by chronic damage. The mdx mouse is a murine model of DMD and develops the same characteristics as dystrophic patients when subjected to chronic exercise. The connective tissue growth factor (CTGF/CCN2) and transforming growth factor type beta (TGF-β), which are overexpressed in muscular dystrophies, play a major role in many progressive scarring conditions. We have tested the hypothesis that ACE inhibition decreases fibrosis in dystrophic skeletal muscle by treatment of mdx mice with the ACE inhibitor enalapril. Both sedentary and exercised mdx mice treated with enalapril showed improvement in gastrocnemius muscle strength explained by a reduction in both muscle damage and ECM accumulation. ACE inhibition decreased CTGF expression in sedentary or exercised mdx mice and diminished CTGF-induced pro-fibrotic activity in a model of CTGF overexpression by adenoviral infection. Enalapril did not have an effect on TGF-β1 expression or its signaling activity in sedentary or exercised dystrophic mice. Thus, ACE inhibition might improve muscle strength and decrease fibrosis by diminishing specifically CTGF expression and activity without affecting TGF-β1 signaling. Our data provide insights into the pathogenic events in dystrophic muscle. We propose ACE as a target for developing therapies for DMD and related diseases.

  6. CTGF Promotes Inflammatory Cell Infiltration of the Renal Interstitium by Activating NF-κB

    PubMed Central

    Sánchez-López, Elsa; Rayego, Sandra; Rodrigues-Díez, Raquel; Rodriguez, Javier Sánchez; Rodrigues-Díez, Raúl; Rodríguez-Vita, Juan; Carvajal, Gisselle; Aroeira, Luiz Stark; Selgas, Rafael; Mezzano, Sergio A.; Ortiz, Alberto; Egido, Jesús; Ruiz-Ortega, Marta

    2009-01-01

    Connective tissue growth factor (CTGF) is an important profibrotic factor in kidney diseases. Blockade of endogenous CTGF ameliorates experimental renal damage and inhibits synthesis of extracellular matrix in cultured renal cells. CTGF regulates several cellular responses, including adhesion, migration, proliferation, and synthesis of proinflammatory factors. Here, we investigated whether CTGF participates in the inflammatory process in the kidney by evaluating the nuclear factor-kappa B (NF-κB) pathway, a key signaling system that controls inflammation and immune responses. Systemic administration of CTGF to mice for 24 h induced marked infiltration of inflammatory cells in the renal interstitium (T lymphocytes and monocytes/macrophages) and led to elevated renal NF-κB activity. Administration of CTGF increased renal expression of chemokines (MCP-1 and RANTES) and cytokines (INF-γ, IL-6, and IL-4) that recruit immune cells and promote inflammation. Treatment with a NF-κB inhibitor, parthenolide, inhibited CTGF-induced renal inflammatory responses, including the up-regulation of chemokines and cytokines. In cultured murine tubuloepithelial cells, CTGF rapidly activated the NF-κB pathway and the cascade of mitogen-activated protein kinases, demonstrating crosstalk between these signaling pathways. CTGF, via mitogen-activated protein kinase and NF-κB activation, increased proinflammatory gene expression. These data show that in addition to its profibrotic properties, CTGF contributes to the recruitment of inflammatory cells in the kidney by activating the NF-κB pathway. PMID:19423687

  7. Role of CTGF gene promoter methylation in the development of hepatic fibrosis

    PubMed Central

    Shi, Cuicui; Li, Guangming; Tong, Yanyan; Deng, Yilin; Fan, Jiangao

    2016-01-01

    Connective tissue growth factor (CTGF) plays a critical role in the hepatic stellate cells (HSCs)-mediated development of hepatic fibrosis. Nevertheless, the effects of CTGF gene promoter methylation in the pathogenesis of hepatic fibrosis remain largely unknown. In the current study, we isolated and overexpressed CTGF in primary HSCs. We analyzed the CTGF gene promoter methylation inHSCs that undergo a phenotypic change into myofibroblast-like cellsthat express α-smooth muscle actin (α-SMA) in vitro and in vivo in a CCl4-induced rat hepatic fibrosis model. We found that CTGF promoted the phenotypic changes of HSCs into myofibroblasts in vitro, while inhibition of CTGF promoter methylation augmented the process, suggesting that CTGF gene promoter methylation may negatively regulate hepatic fibrosis. In vivo, CCl4 induced hepatic fibrosis in rats, and the severity of hepatic fibrosis inversely correlated with the levels of CTGF gene promoter methylation in HSCs. Together, our data demonstrate that CTGF gene promoter methylation may prevent the development of hepatic fibrosis, and low level of CTGF gene promoter methylation in HSCs may be a predisposing factor for developing liver fibrotic disease. PMID:27069546

  8. Correlation of CTGF gene promoter methylation with CTGF expression in type 2 diabetes mellitus with or without nephropathy.

    PubMed

    Zhang, Hao; Cai, Xu; Yi, Bin; Huang, Jing; Wang, Jianwen; Sun, Jian

    2014-06-01

    Increasing evidence shows that DNA methylation is involved in the development and progression of diabetes mellitus (DM) and its complications. Previous studies conducted by our group have indicated that high glucose levels may induce the demethylation process of the connective tissue growth factor (CTGF) gene promoter and increase the expression of CTGF in human glomerular mesangial cells. Based on these findings, the aim of the present study was to investigate the methylation level of genomic DNA and the CTGF promoter in patients with type 2 DM and to analyze its possible correlation with CTGF expression. Methylation levels of the whole genomic DNA were detected by high-performance liquid chromatography in a non-diabetes control (NDM) group (n=29), a diabetes without nephropathy (NDN) group (n=37) and a diabetes with nephropathy (DN) group (n=38). CTGF promoter methylation levels were detected by methylation-specific polymerase chain reaction and bisulfite sequencing. The levels of serum CTGF were assessed using the enzyme-linked immunosorbent assay. The methylation levels of the whole genomic DNA were not significantly different among the three groups. However, the CTGF methylation levels in the two diabetes groups were significantly lower than those in the NDM group (P<0.05), with the lowest methylation level in the DN group (P<0.05). The CTGF protein levels in the DN group were significantly higher than those in the NDM and NDN groups (P<0.05). Levels of CTGF were negatively correlated with the estimated glomerular filtration rate (eGFR) and the methylation level of the promoter, while they were positively correlated with age, urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen, creatinine, fasting blood sugar and postprandial blood glucose. Multiple stepwise regression analysis showed that CTGF expression was associated with the UACR, CTGF methylation level and eGFR. DNA methylation is a regulatory mechanism of CTGF expression, which is decreased

  9. Modulation of the TGF{beta}/Smad signaling pathway in mesangial cells by CTGF/CCN2

    SciTech Connect

    Abdel Wahab, Nadia . E-mail: nadia.wahab@imperial.ac.uk; Weston, Benjamin S.; Mason, Roger M.

    2005-07-15

    Transforming growth factor-beta (TGF{beta}) drives fibrosis in diseases such as diabetic nephropathy (DN). Connective tissue growth factor (CTGF; CCN2) has also been implicated in this, but the molecular mechanism is unknown. We show that CTGF enhances the TGF{beta}/Smad signaling pathway by transcriptional suppression of Smad 7 following rapid and sustained induction of the transcription factor TIEG-1. Smad 7 is a known antagonist of TGF{beta} signaling and TIEG-1 is a known repressor of Smad 7 transcription. CTGF enhanced TGF{beta}-induced phosphorylation and nuclear translocation of Smad 2 and Smad 3 in mesangial cells. Antisense oligonucleotides directed against TIEG-1 prevented CTGF-induced downregulation of Smad 7. CTGF enhanced TGF{beta}-stimulated transcription of the SBE4-Luc reporter gene and this was markedly reduced by TIEG-1 antisense oligonucleotides. Expression of the TGF{beta}-responsive genes PAI-1 and Col III over 48 h was maximally stimulated by TGF{beta} + CTGF compared to TGF{beta} alone, while CTGF alone had no significant effect. TGF{beta}-stimulated expression of these genes was markedly reduced by both CTGF and TIEG-1 antisense oligonucleotides, consistent with the endogenous induction of CTGF by TGF{beta}. We propose that under pathological conditions, where CTGF expression is elevated, CTGF blocks the negative feedback loop provided by Smad 7, allowing continued activation of the TGF{beta} signaling pathway.

  10. Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy.

    PubMed

    Morales, Maria Gabriela; Gutierrez, Jaime; Cabello-Verrugio, Claudio; Cabrera, Daniel; Lipson, Kenneth E; Goldschmeding, Roel; Brandan, Enrique

    2013-12-15

    In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.

  11. Hypomethylation of the CTGF gene locus is a common feature of paediatric pre-B acute lymphoblastic leukaemia.

    PubMed

    Welch, Mathew D; Greene, Wayne K; Kees, Ursula R

    2013-08-01

    The connective tissue growth factor gene (CTGF) is aberrantly expressed in 75% of precursor B-cell acute lymphoblastic leukaemias (pre-B ALL) and is associated with poor outcome. We identified consistent hypomethylation of the CTGF locus in primary pre-B ALL specimens regardless of CTGF expression. By contrast, primary T-cell ALL specimens, which do not express CTGF, exhibited distinctive patterns of hypermethylation. Furthermore, we confirmed that global changes in DNA methylation and histone acetylation can both functionally modulate CTGF expression in pre-B ALL cell lines. These data suggest that hypomethylation of the CTGF locus is an essential prerequisite for aberrant CTGF expression in pre-B ALL.

  12. BMP Signaling and Podocyte Markers Are Decreased in Human Diabetic Nephropathy in Association With CTGF Overexpression

    PubMed Central

    Turk, Tamara; Leeuwis, Jan Willem; Gray, Julia; Torti, Suzy V.; Lyons, Karen M.; Nguyen, Tri Q.; Goldschmeding, Roel

    2009-01-01

    Diabetic nephropathy is characterized by decreased expression of bone morphogenetic protein-7 (BMP-7) and decreased podocyte number and differentiation. Extracellular antagonists such as connective tissue growth factor (CTGF; CCN-2) and sclerostin domain-containing-1 (SOSTDC1; USAG-1) are important determinants of BMP signaling activity in glomeruli. We studied BMP signaling activity in glomeruli from diabetic patients and non-diabetic individuals and from control and diabetic CTGF+/+ and CTGF+/− mice. BMP signaling activity was visualized by phosphorylated Smad1, -5, and -8 (pSmad1/5/8) immunostaining, and related to expression of CTGF, SOSTDC1, and the podocyte differentiation markers WT1, synaptopodin, and nephrin. In control and diabetic glomeruli, pSmad1/5/8 was mainly localized in podocytes, but both number of positive cells and staining intensity were decreased in diabetes. Nephrin and synaptopodin were decreased in diabetic glomeruli. Decrease of pSmad1/5/8 was only partially explained by decrease in podocyte number. SOSTDC1 and CTGF were expressed exclusively in podocytes. In diabetic glomeruli, SOSTDC1 decreased in parallel with podocyte number, whereas CTGF was strongly increased. In diabetic CTGF+/− mice, pSmad1/5/8 was preserved, compared with diabetic CTGF+/+ mice. In conclusion, in human diabetic nephropathy, BMP signaling activity is diminished, together with reduction of podocyte markers. This might relate to concomitant overexpression of CTGF but not SOSTDC1. (J Histochem Cytochem 57:623–631, 2009) PMID:19255250

  13. The CTGF -945GC polymorphism is not associated with plasma CTGF and does not predict nephropathy or outcome in type 1 diabetes

    PubMed Central

    2011-01-01

    The -945GC polymorphism (rs6918698) in the connective tissue growth factor gene promoter (CTGF/CCN-2) has been associated with end organ damage in systemic sclerosis. Because CTGF is important in progression of diabetic kidney disease, we investigated whether the -945GC polymorphism is associated with plasma CTGF level and outcome in type 1 diabetes. The study cohort consisted of 448 diabetic nephropathy patients and 419 normoalbuminuric diabetic patients with complete data concerning renal function and cardiovascular characteristics. Genomic DNA was genotyped by a QPCR-based SNP assay. We observed no relation between the -945GC polymorphism and plasma CTGF level, and the genotype frequencies were not different in nephropathy patients vs. normoalbuminuric controls. General and cardiovascular mortality, and renal function decline was similar in patients with CC, CG or GG genotypes. In conclusion, the -945GC SNP does not affect plasma CTGF levels, incidence and prognosis of diabetic nephropathy, and cardiovascular outcome. PMID:21548990

  14. The CTGF -945GC polymorphism is not associated with plasma CTGF and does not predict nephropathy or outcome in type 1 diabetes.

    PubMed

    Dendooven, Amélie; Nguyen, Tri Q; Brosens, Lodewijk; Li, Dongxia; Tarnow, Lise; Parving, Hans-Henrik; Rossing, Peter; Goldschmeding, Roel

    2011-05-08

    The -945GC polymorphism (rs6918698) in the connective tissue growth factor gene promoter (CTGF/CCN-2) has been associated with end organ damage in systemic sclerosis. Because CTGF is important in progression of diabetic kidney disease, we investigated whether the -945GC polymorphism is associated with plasma CTGF level and outcome in type 1 diabetes. The study cohort consisted of 448 diabetic nephropathy patients and 419 normoalbuminuric diabetic patients with complete data concerning renal function and cardiovascular characteristics. Genomic DNA was genotyped by a QPCR-based SNP assay. We observed no relation between the -945GC polymorphism and plasma CTGF level, and the genotype frequencies were not different in nephropathy patients vs. normoalbuminuric controls. General and cardiovascular mortality, and renal function decline was similar in patients with CC, CG or GG genotypes. In conclusion, the -945GC SNP does not affect plasma CTGF levels, incidence and prognosis of diabetic nephropathy, and cardiovascular outcome.

  15. CCN Family 2/Connective Tissue Growth Factor (CCN2/CTGF) Promotes Osteoclastogenesis via Induction of and Interaction with Dendritic Cell–Specific Transmembrane Protein (DC-STAMP)

    PubMed Central

    Nishida, Takashi; Emura, Kenji; Kubota, Satoshi; Lyons, Karen M; Takigawa, Masaharu

    2013-01-01

    CCN family 2/connective tissue growth factor (CCN2/CTGF) promotes endochondral ossification. However, the role of CCN2 in the replacement of hypertrophic cartilage with bone is still unclear. The phenotype of Ccn2 null mice, having an expanded hypertrophic zone, indicates that the resorption of the cartilage extracellular matrix is impaired therein. Therefore, we analyzed the role of CCN2 in osteoclastogenesis because cartilage extracellular matrix is resorbed mainly by osteoclasts during endochondral ossification. Expression of the Ccn2 gene was upregulated in mouse macrophage cell line RAW264.7 on day 6 after treatment of glutathione S transferase (GST) fusion mouse receptor activator of NF-κB ligand (GST-RANKL), and a combination of recombinant CCN2 (rCCN2) and GST-RANKL significantly enhanced tartrate-resistant acid phosphatase (TRACP)–positive multinucleated cell formation compared with GST-RANKL alone. Therefore, we suspected the involvement of CCN2 in cell-cell fusion during osteoclastogenesis. To clarify the mechanism, we performed real-time PCR analysis of gene expression, coimmunoprecipitation analysis, and solid-phase binding assay of CCN2 and dendritic cell–specific transmembrane protein (DC-STAMP), which is involved in cell-cell fusion. The results showed that CCN2 induced and interacted with DC-STAMP. Furthermore, GST-RANKL–induced osteoclastogenesis was impaired in fetal liver cells from Ccn2 null mice, and the impaired osteoclast formation was rescued by the addition of exogenous rCCN2 or the forced expression of DC-STAMP by a retroviral vector. These results suggest that CCN2 expressed during osteoclastogenesis promotes osteoclast formation via induction of and interaction with DC-STAMP. PMID:20721934

  16. Mechanical stretch increases CCN2/CTGF expression in anterior cruciate ligament-derived cells

    SciTech Connect

    Miyake, Yoshiaki; Furumatsu, Takayuki; Kubota, Satoshi; Kawata, Kazumi; Ozaki, Toshifumi; Takigawa, Masaharu

    2011-06-03

    Highlights: {yields} CCN2/CTGF localizes to the ligament-to-bone interface, but is not to the midsubstance region of human anterior cruciate ligament (ACL). {yields} Mechanical stretch induces higher increase of CCN2/CTGF gene expression and protein secretion in ACL interface cells compared with ACL midsubstance cells. {yields} CCN2/CTGF treatment stimulates the proliferation of ACL interface cells. -- Abstract: Anterior cruciate ligament (ACL)-to-bone interface serves to minimize the stress concentrations that would arise between two different tissues. Mechanical stretch plays an important role in maintaining cell-specific features by inducing CCN family 2/connective tissue growth factor (CCN2/CTGF). We previously reported that cyclic tensile strain (CTS) stimulates {alpha}1(I) collagen (COL1A1) expression in human ACL-derived cells. However, the biological function and stress-related response of CCN2/CTGF were still unclear in ACL fibroblasts. In the present study, CCN2/CTGF was observed in ACL-to-bone interface, but was not in the midsubstance region by immunohistochemical analyses. CTS treatments induced higher increase of CCN2/CTGF expression and secretion in interface cells compared with midsubstance cells. COL1A1 expression was not influenced by CCN2/CTGF treatment in interface cells despite CCN2/CTGF stimulated COL1A1 expression in midsubstance cells. However, CCN2/CTGF stimulated the proliferation of interface cells. Our results suggest that distinct biological function of stretch-induced CCN2/CTGF might regulate region-specific phenotypes of ACL-derived cells.

  17. MicroRNA-26b attenuates monocrotaline-induced pulmonary vascular remodeling via targeting connective tissue growth factor (CTGF) and cyclin D1 (CCND1)

    PubMed Central

    Zhou, Sijing; Li, Min; Sun, Li; Xu, Xuan; Fei, Guanghe

    2016-01-01

    MicroRNAs are involved in the control of cell growth, and deregulated pulmonary artery smooth muscle cell proliferation plays an essential role in the development of pulmonary hypertension. The objective of this study was to identify differentially expressed microRNA(s) and explore its therapeutic role in treatment of the disease. MicroRNA expression profile analysis showed microRNA-26b was differentially expressed in pulmonary artery smooth muscle cells harvested from monocrotaline-treated rats, and we validated microRNA-26b targets, in vitro and in vivo, CTGF and CCND1, both of which have been shown, in our previous work, to be involved in the pathogenesis of pulmonary hypertension. In vivo experiments demonstrated monocrotaline-induced pulmonary artery remodeling could be almost completely abolished by administration of microRNA-26b, while CTGF or CCND1 shRNA significantly, but only partially, attenuated the remodeling by silencing the designed target. Additionally, exogenous expression of the microRNA-26b substantially downregulated CTGF and CCND1 in human pulmonary artery smooth muscle cells. MicroRNA-26b might be a potent therapeutic tool to treat pulmonary hypertension. PMID:27322082

  18. Microrna-26b attenuates monocrotaline-induced pulmonary vascular remodeling via targeting connective tissue growth factor (CTGF) and cyclin D1 (CCND1).

    PubMed

    Wang, Ran; Ding, Xing; Zhou, Sijing; Li, Min; Sun, Li; Xu, Xuan; Fei, Guanghe

    2016-11-08

    MicroRNAs are involved in the control of cell growth, and deregulated pulmonary artery smooth muscle cell proliferation plays an essential role in the development of pulmonary hypertension. The objective of this study was to identify differentially expressed microRNA(s) and explore its therapeutic role in treatment of the disease. MicroRNA expression profile analysis showed microRNA-26b was differentially expressed in pulmonary artery smooth muscle cells harvested from monocrotaline-treated rats, and we validated microRNA-26b targets, in vitro and in vivo, CTGF and CCND1, both of which have been shown, in our previous work, to be involved in the pathogenesis of pulmonary hypertension. In vivo experiments demonstrated monocrotaline-induced pulmonary artery remodeling could be almost completely abolished by administration of microRNA-26b, while CTGF or CCND1 shRNA significantly, but only partially, attenuated the remodeling by silencing the designed target. Additionally, exogenous expression of the microRNA-26b substantially downregulated CTGF and CCND1 in human pulmonary artery smooth muscle cells. MicroRNA-26b might be a potent therapeutic tool to treat pulmonary hypertension.

  19. Molecular requirements for induction of CTGF expression by TGF-beta1 in primary osteoblasts.

    PubMed

    Arnott, J A; Zhang, X; Sanjay, A; Owen, T A; Smock, S L; Rehman, S; DeLong, W G; Safadi, F F; Popoff, S N

    2008-05-01

    Connective tissue growth factor (CTGF/CCN2) is a cysteine rich, extracellular matrix protein that acts as an anabolic growth factor to regulate osteoblast differentiation and function. In osteoblasts, CTGF is induced by TGF-beta1 where it acts as a downstream mediator of TGF-beta1 induced matrix production. The molecular mechanisms that control CTGF induction by TGF-beta1 in osteoblasts are not known. To assess the role of individual Smads in mediating the induction of CTGF by TGF-beta1, we used specific Smad siRNAs to block Smad expression. These studies demonstrated that Smads 3 and 4, but not Smad 2, are required for TGF-beta1 induced CTGF promoter activity and expression in osteoblasts. Since the activation of MAPKs (Erk, Jnk and p38) by TGF-beta1 is cell type specific, we were interested in determining the role of individual MAPKs in TGF-beta1 induction of CTGF promoter activity and expression. Using dominant negative (DN) mutants for Erk, Jnk and p38, we demonstrated that the expression of DN-Erk caused a significant inhibition of TGF-beta1 induced CTGF promoter activity. In contrast, the expression of DN-p38 or DN-Jnk failed to inhibit activation of CTGF promoter activity. To confirm the vital role of Erk, we used the Erk inhibitor (PD98059) to block its activation, demonstrating that it prevented TGF-beta1 activation of the CTGF promoter and up-regulation of CTGF expression in osteoblasts. Since Src can also act as a downstream signaling effector for TGF-beta in some cell types, we determined its role in TGF-beta1 induction of CTGF in osteoblasts. Treatment of osteoblasts with a Src family kinase inhibitor, PP2, or the expression of two independent kinase-dead Src mutant constructs caused significant inhibition of TGF-beta1 induced CTGF promoter activity and expression. Additionally, blocking Src activation prevented Erk activation by TGF-beta1 demonstrating a role for Src as an upstream mediator of Erk in regulating CTGF expression in osteoblasts. To

  20. Hyaluronic acid modulates gene expression of connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-beta1), and vascular endothelial growth factor (VEGF) in human fibroblast-like synovial cells from advanced-stage osteoarthritis in vitro.

    PubMed

    Lee, Yu-Tsang; Shao, Hung-Jen; Wang, Jyh-Horng; Liu, Haw-Chang; Hou, Sheng-Mou; Young, Tai-Horng

    2010-04-01

    Intraarticular injection of hyaluronan (hyaluronic acid; HA) is the common way to treat osteoarthritis (OA) of knees. This treatment cannot only maintain the viscoelastic properties of knee but also release the OA pain. However, the exact molecular mechanism is unknown. In this study, after human synovial cells were stimulated with HA and Hylan (Synvisc) for 24 h, real-time polymerase chain reaction (real-time PCR) was used to detect the alteration of connective tissue growth factor (CTGF), transforming growth factor-beta1 (TGF-beta1), and vascular endothelial growth factor (VEGF) gene expression, which were specific genes related to pathogenesis of OA knees. Our results illustrated that both HA and Hylan might not cause cytotoxicity or apoptosis of synovial cells in serum deprivation environment. The gene expressions of TGF-beta1 and VEGF were significantly increased at the concentration of 0.1 mg/mL HA and 0.1 mg/mL Hylan, respectively (alpha < 0.05). The synovial cells with treatment of 0.1 mg/mL Hylan decreased the CTGF gene expression (0.66-fold) and VEGF (0.78-fold) compared to 0.1 mg/mL HA (alpha < 0.05). We suggested that the profile of CTGF, TGF-beta1, and VEGF gene expressions in our study might provide the rational mechanism for the therapeutic effect of hyaluronan on OA knees.

  1. CTGF promotes osteosarcoma angiogenesis by regulating miR-543/angiopoietin 2 signaling.

    PubMed

    Wang, Li-Hong; Tsai, Hsiao-Chi; Cheng, Yu-Che; Lin, Chih-Yang; Huang, Yuan-Li; Tsai, Chun-Hao; Xu, Guo-Hong; Wang, Shih-Wei; Fong, Yi-Chin; Tang, Chih-Hsin

    2017-04-10

    Osteosarcoma is the most common primary solid tumor of bone. It has a high metastatic potential and occurs predominantly in adolescents and young adults. Angiopoietin 2 (Angpt2) is a key regulator in tumor angiogenesis, facilitating tumor growth and metastasis. Connective tissue growth factor (CTGF, also known as CCN2), is a cysteine-rich protein that has been reported to promote metastasis of osteosarcoma. However, the effect of CTGF on Angpt2 regulation and angiogenesis in human osteosarcoma remains largely unknown. We found that overexpression of CTGF in osteosarcoma cells increased Angpt2 production and induced angiogenesis, in vitro and in vivo. Our findings demonstrate that CTGF-enhanced Angpt2 expression and angiogenesis is mediated by the phospholipase C (PLC)/protein kinase C (PKCδ) signaling pathway. Moreover, endogenous microRNA-543 (miR-543) expression was negatively regulated by CTGF via the PLC/PKCδ pathway. We also provide evidence showing clinical significance between CTGF, Angpt2, and miR-543 as well as tumor staging in human osteosarcoma tissue. CTGF may serve as a therapeutic target in the process of osteosarcoma metastasis and angiogenesis.

  2. Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

    PubMed Central

    Zhao, Zhen; Sheng, Jianting; Wang, Jiang; Liu, Jiyong; Cui, Kemi; Chang, Jenny; Zhao, Hong; Wong, Stephen

    2015-01-01

    Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression. PMID:26318291

  3. Role of CTGF in White Matter Development in Tuberous Sclerosis

    DTIC Science & Technology

    2016-04-01

    which lacks Tsc1 expression only in neurons. Here we show that, neurons lacking Tsc1 secrete excessive amounts of connective tissue growth factor...that, neurons lacking Tsc1 secrete excessive amounts of connective tissue growth factor (CTGF), which in turn blocks the maturation of...Kennedy, L., and Leask, A. (2008). Connective tissue growth factor promoter activity in normal and wounded skin. Fibrogenesis & tissue repair 1, 3. Kim

  4. CREB trans-activation of disruptor of telomeric silencing-1 mediates forskolin inhibition of CTGF transcription in mesangial cells.

    PubMed

    Yu, Zhiyuan; Kong, Qun; Kone, Bruce C

    2010-03-01

    Connective tissue growth factor (CTGF) participates in diverse fibrotic processes including glomerulosclerosis. The adenylyl cyclase agonist forskolin inhibits CTGF expression in mesangial cells by unclear mechanisms. We recently reported that the histone H3K79 methyltransferase disruptor of telomeric silencing-1 (Dot1) suppresses CTGF gene expression in collecting duct cells (J Clin Invest 117: 773-783, 2007) and HEK 293 cells (J Biol Chem In press). In the present study, we characterized the involvement of Dot1 in mediating the inhibitory effect of forskolin on CTGF transcription in mouse mesangial cells. Overexpression of Dot1 or treatment with forskolin dramatically suppressed basal CTGF mRNA levels and CTGF promoter-luciferase activity, while hypermethylating H3K79 in chromatin associated with the CTGF promoter. siRNA knockdown of Dot1 abrogated the inhibitory effect of forskolin on CTGF mRNA expression. Analysis of the Dot1 promoter sequence identified a CREB response element (CRE) at -384/-380. Overexpression of CREB enhanced forskolin-stimulated Dot1 promoter activity. A constitutively active CREB mutant (CREB-VP16) strongly induced Dot1 promoter-luciferase activity, whereas overexpression of CREBdLZ-VP16, which lacks the CREB DNA-binding domain, abolished this activation. Mutation of the -384/-380 CRE resulted in 70% lower levels of Dot1 promoter activity. ChIP assays confirmed CREB binding to the Dot1 promoter in chromatin. We conclude that forskolin stimulates CREB-mediated trans-activation of the Dot1 gene, which leads to hypermethylation of histone H3K79 at the CTGF promoter, and inhibition of CTGF transcription. These data are the first to describe regulation of the Dot1 gene, and disclose a complex network of genetic and epigenetic controls on CTGF transcription.

  5. High glucose-induced cytoplasmic translocation of Dnmt3a contributes to CTGF hypo-methylation in mesangial cells

    PubMed Central

    Zhang, Hao; Li, Aimei; Zhang, Wei; Huang, Zhijun; Wang, Jianwen; Yi, Bin

    2016-01-01

    Connective tissue growth factor (CTGF) plays an essential role in the pathogenesis of diabetic nephropathy and we have previously identified that high glucose induced the expression of CTGF by decreasing DNA methylation. The aim of the present study was to investigate the underlying mechanisms of the high glucose-induced CTGF hypo-methylation. Human glomerular mesangial cells (hMSCs) were treated with low glucose (5 mM), mannitol (30 mM) or high glucose (30 mM) respectively. Immunofluorescence staining, real-time quantitative PCR and western blotting were performed to determine the subcellular distribution and expression of CTGF and Dnmt3a. ChIP-PCR assay was applied to investigate the capability of Dnmt3a to bind the CpG island of CTGF. Our results showed that high glucose induced both mRNA and protein expressions of CTGF, and led to increased cytoplasmic translocation of Dnmt3a in cultured hMSCs. The nuclear Dnmt3a protein was significantly reduced after high glucose treatment, although the expression of total Dnmt3a protein was not altered. We further discovered that ERK/MAPK signalling contributed to the high glucose-induced cytoplasmic translocation of Dnmt3a. Consequently, less Dnmt3a protein was bound to the CpG island of CTGF promoter, which induced an increase in CTGF expression by epigenetic regulation in the presence of high glucose. In conclusion, high glucose induces cytoplasmic translocation of Dnmt3a, possibly through activating ERK/MAPK signalling pathway, which contributes to the decreased binding of Dnmt3a on CTGF promoter and the subsequent CTGF hypo-methylation in diabetic nephropathy. PMID:27364355

  6. Involvement of Connective Tissue Growth Factor (CTGF) in Insulin-like Growth Factor-I (IGF1) Stimulation of Proliferation of a Bovine Mammary Epithelial Cell Line

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin-like growth factor I (IGF1) plays an important role in mammary gland development and lactation in part by stimulating proliferation of the milk-producing epithelial cells. In this study, we used the bovine mammary epithelial cell line MAC-T cells as a model to understand the mechanism by whi...

  7. CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth

    PubMed Central

    Capparelli, Claudia; Whitaker-Menezes, Diana; Guido, Carmela; Balliet, Renee; Pestell, Timothy G.; Howell, Anthony; Sneddon, Sharon; Pestell, Richard G.; Martinez-Outschoorn, Ubaldo; Lisanti, Michael P.; Sotgia, Federica

    2012-01-01

    Previous studies have demonstrated that loss of caveolin-1 (Cav-1) in stromal cells drives the activation of the TGF-β signaling, with increased transcription of TGF-β target genes, such as connective tissue growth factor (CTGF). In addition, loss of stromal Cav-1 results in the metabolic reprogramming of cancer-associated fibroblasts, with the induction of autophagy and glycolysis. However, it remains unknown if activation of the TGF-β / CTGF pathway regulates the metabolism of cancer-associated fibroblasts. Therefore, we investigated whether CTGF modulates metabolism in the tumor microenvironment. For this purpose, CTGF was overexpressed in normal human fibroblasts or MDA-MB-231 breast cancer cells. Overexpression of CTGF induces HIF-1α-dependent metabolic alterations, with the induction of autophagy/mitophagy, senescence, and glycolysis. Here, we show that CTGF exerts compartment-specific effects on tumorigenesis, depending on the cell-type. In a xenograft model, CTGF overexpressing fibroblasts promote the growth of co-injected MDA-MB-231 cells, without any increases in angiogenesis. Conversely, CTGF overexpression in MDA-MB-231 cells dramatically inhibits tumor growth in mice. Intriguingly, increased extracellular matrix deposition was seen in tumors with either fibroblast or MDA-MB-231 overexpression of CTGF. Thus, the effects of CTGF expression on tumor formation are independent of its extracellular matrix function, but rather depend on its ability to activate catabolic metabolism. As such, CTGF-mediated induction of autophagy in fibroblasts supports tumor growth via the generation of recycled nutrients, whereas CTGF-mediated autophagy in breast cancer cells suppresses tumor growth, via tumor cell self-digestion. Our studies shed new light on the compartment-specific role of CTGF in mammary tumorigenesis, and provide novel insights into the mechanism(s) generating a lethal tumor microenvironment in patients lacking stromal Cav-1. As loss of Cav-1 is a

  8. Cartilage–Specific Over-Expression of CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Stimulates Insulin-Like Growth Factor Expression and Bone Growth

    PubMed Central

    Tomita, Nao; Hattori, Takako; Itoh, Shinsuke; Aoyama, Eriko; Yao, Mayumi; Yamashiro, Takashi; Takigawa, Masaharu

    2013-01-01

    Previously we showed that CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro. To elucidate the specific role and molecular mechanism of CCN2 in cartilage development in vivo, in the present study we generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed histologically and immunohistologically and also by micro CT. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage–related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation. Micro-CT analysis of transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA. The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR. Our data indicates that the observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. These findings indicate that CCN2-overexpression in

  9. CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer

    PubMed Central

    Yang, Kai; Gao, Kai; Hu, Gui; Wen, Yanguang; Lin, Changwei; Li, Xiaorong

    2016-01-01

    Colorectal cancer (CRC) is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU) is one of a doctors’ first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF) is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL) and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU-mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC. PMID:27942222

  10. Angiotensin II receptor type 1 blockade decreases CTGF/CCN2-mediated damage and fibrosis in normal and dystrophic skeletal muscles

    PubMed Central

    Cabello-Verrugio, Claudio; Morales, María Gabriela; Cabrera, Daniel; Vio, Carlos P; Brandan, Enrique

    2012-01-01

    Abstract Connective tissue growth factor (CTGF/CCN-2) is mainly involved in the induction of extracellular matrix (ECM) proteins. The levels of CTGF correlate with the degree and severity of fibrosis in many tissues, including dystrophic skeletal muscle. The CTGF overexpression in tibialis anterior skeletal muscle using an adenoviral vector reproduced many of the features observed in dystrophic muscles including muscle damage and regeneration, fibrotic response and decrease in the skeletal muscle strength. The renin–angiotensin system is involved in the genesis and progression of fibrotic diseases through its main fibrotic components angiotensin-II and its transducer receptor AT-1. The use of AT-1 receptor blockers (ARB) has been shown to decrease fibrosis. In this paper, we show the effect of AT-1 receptor blockade on CTGF-dependent biological activity in skeletal muscle cells as well as the response to CTGF overexpression in normal skeletal muscle. Our results show that in myoblasts ARB decreased CTGF-mediated increase of ECM protein levels, extracellular signal regulated kinases 1/2 (ERK-1/2) phosphorylation and stress fibres formation. In tibialis anterior muscle overexpressing CTGF using an adenovirus, ARB treatment decreased CTGF-mediated increase of ECM molecules, α-SMA and ERK-1/2 phosphorylation levels. Quite remarkable, ARB was able to prevent the loss of contractile force of tibialis anterior muscles overexpressing CTGF. Finally, we show that ARB decreased the levels of fibrotic proteins, CTGF and ERK-1/2 phosphorylation augmented in a dystrophic skeletal muscle from mdx mice. We propose that ARB is a novel pharmacological tool that can be used to decrease the fibrosis induced by CTGF in skeletal muscle associated with muscular dystrophies. PMID:21645240

  11. MiR-143 targets CTGF and exerts tumor-suppressing functions in epithelial ovarian cancer

    PubMed Central

    Wang, Lufei; He, Jin; Xu, Hongmei; Xu, Longjie; Li, Na

    2016-01-01

    A series of recent studies suggested that miR-143 might involve in the tumorigenesis and metastasis of various cancer types. However, the biological function and underlying mechanisms of miR-143 in human epithelial ovarian carcinoma (EOC) remain unknown. Therefore, this study aimed to investigate the miR-143 expression and its clinical diagnosis significance in patients suffering EOC and to analyze its role and underlying molecular mechanism in EOC. Our result showed that the expression levels of miR-143 were downregulated in EOC tissues and cell lines, was associated with International Federation of Gynaecology and Obstetrics (FIGO) stage, pathological grade and lymph node metastasis (all P < 0.01) . Overexpression of miR-143 significantly inhibited EOC cell proliferation, migration, and invasion. Furthermore, computational algorithm combined with luciferase reporter assays identified connective tissue growth factor (CTGF) as the direct target of miR-143 in EOC cells. The expression level of CTGF was significantly increased in EOC tissues, was inversely correlated with miR-143 expression in clinical EOC tissues. Knockdown of CTGF mimicked the suppression effect induced by miR-143 overexpression. Restoration of CTGF expression partially reversed the suppression effect induced by miR-143 overexpression. These results suggested that miR-143 inhibited EOC cell proliferation, migration, and invasion, at least in part, via suppressing CTGF expression. PMID:27398154

  12. EGCG inhibits CTGF expression via blocking NF-κB activation in cardiac fibroblast.

    PubMed

    Cai, Yi; Yu, Shan-Shan; Chen, Ting-Ting; Gao, Si; Geng, Biao; Yu, Yang; Ye, Jian-Tao; Liu, Pei-Qing

    2013-01-15

    Connective tissue growth factor (CTGF) has been reported to play an important role in tissue fibrosis and presents a promising therapeutic target for fibrotic diseases. In heart, inappropriate increase in level of CTGF promotes fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby exacerbating cardiac hypertrophy and subsequent failure. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac fibrosis. However, the molecular mechanism by which EGCG exerts its anti-fibrotic effects has not been well investigated. In this study, we found that EGCG could significantly reduce collagen synthesis, fibronectin (FN) expression and cell proliferation in rat cardiac fibroblasts stimulated with angiotensinII (AngII). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, EGCG attenuated the excessive expression of CTGF induced by AAC or AngII, and reduced the nuclear translocation of NF-κB p65 subunit and degradation of IκB-α. Subsequently, we demonstrated that in cardiac fibroblasts NF-κB inhibition could suppress AngII-induced CTGF expression. Taken together, these findings provide the first evidence that the effect of EGCG against cardiac fibrosis may be attributed to its inhibition on NF-κB activation and subsequent CTGF overexpression, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy.

  13. Pasteurella multocida toxin (PMT) upregulates CTGF which leads to mTORC1 activation in Swiss 3T3 cells.

    PubMed

    Oubrahim, Hammou; Wong, Allison; Wilson, Brenda A; Chock, P Boon

    2013-05-01

    Pasteurella multocida toxin (PMT) is a mitogenic protein that hijacks cellular signal transduction pathways via deamidation of heterotrimeric G proteins. We previously showed that rPMT activates mTOR signaling via a Gαq/11/PLCβ/PKC mediated pathway, leading in part to cell proliferation and migration. Herein, we show that mTOR and MAPK, but not membrane-associated tyrosine kinases, are activated in serum-starved 3T3 cells by an autocrine/paracrine substance(s) secreted into the conditioned medium following rPMT treatment. Surprisingly, this diffusible factor(s) is capable of activating mTOR and MAPK pathways even in MEF Gαq/11 double knockout cells. Microarray analysis identified connective tissue growth factor (CTGF) mRNA as the most upregulated gene in rPMT-treated serum-starved 3T3 cells relative to untreated cells. These results were further confirmed using RT-PCR and Western blot analyses. In accord with rPMT-induced mTOR activation, upregulation of CTGF protein was observed in WT MEF, but not in Gαq/11 double knockout MEF cells. Although CTGF expression is regulated by TGFβ, rPMT did not activate TGFβ pathway. In addition, MEK inhibitors U0126 or PD98059, but not mTOR specific inhibitors, rapamycin and Torin 1, inhibited rPMT-induced upregulation of CTGF. Importantly, CTGF overexpression in serum-starved 3T3 cells using adenovirus led to phosphorylation of ribosomal protein S6, a downstream target of mTOR. However, despite the ability of CTGF to activate the mTOR pathway, upregulation of CTGF alone could not induce morphological changes as those observed in rPMT-treated cells. Our findings reveal that CTGF plays an important role, but there are additional factors involved in the mitogenic action of PMT.

  14. Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis

    PubMed Central

    Toda, Naohiro; Mori, Kiyoshi; Kasahara, Masato; Ishii, Akira; Koga, Kenichi; Ohno, Shoko; Mori, Keita P.; Kato, Yukiko; Osaki, Keisuke; Kuwabara, Takashige; Kojima, Katsutoshi; Taura, Daisuke; Sone, Masakatsu; Matsusaka, Taiji; Nakao, Kazuwa; Mukoyama, Masashi; Yanagita, Motoko; Yokoi, Hideki

    2017-01-01

    Connective tissue growth factor (CTGF) coordinates the signaling of growth factors and promotes fibrosis. Neonatal death of systemic CTGF knockout (KO) mice has hampered analysis of CTGF in adult renal diseases. We established 3 types of CTGF conditional KO (cKO) mice to investigate a role and source of CTGF in anti-glomerular basement membrane (GBM) glomerulonephritis. Tamoxifen-inducible systemic CTGF (Rosa-CTGF) cKO mice exhibited reduced proteinuria with ameliorated crescent formation and mesangial expansion in anti-GBM nephritis after induction. Although CTGF is expressed by podocytes at basal levels, podocyte-specific CTGF (pod-CTGF) cKO mice showed no improvement in renal injury. In contrast, PDGFRα promoter-driven CTGF (Pdgfra-CTGF) cKO mice, which predominantly lack CTGF expression by mesangial cells, exhibited reduced proteinuria with ameliorated histological changes. Glomerular macrophage accumulation, expression of Adgre1 and Ccl2, and ratio of M1/M2 macrophages were all reduced both in Rosa-CTGF cKO and Pdgfra-CTGF cKO mice, but not in pod-CTGF cKO mice. TGF-β1-stimulated Ccl2 upregulation in mesangial cells and macrophage adhesion to activated mesangial cells were decreased by reduction of CTGF. These results reveal a novel mechanism of macrophage migration into glomeruli with nephritis mediated by CTGF derived from mesangial cells, implicating the therapeutic potential of CTGF inhibition in glomerulonephritis. PMID:28191821

  15. Src is a major signaling component for CTGF induction by TGF-beta1 in osteoblasts.

    PubMed

    Zhang, X; Arnott, J A; Rehman, S; Delong, W G; Sanjay, A; Safadi, F F; Popoff, S N

    2010-09-01

    Connective tissue growth factor (CTGF/CCN2) is induced by transforming growth factor beta1 (TGF-beta1) where it acts as a downstream mediator of TGF-beta1 induced matrix production in osteoblasts. We have shown the requirement of Src, Erk, and Smad signaling for CTGF induction by TGF-beta1 in osteoblasts; however, the potential interaction among these signaling pathways remains undetermined. In this study we demonstrate that TGF-beta1 activates Src kinase in ROS17/2.8 cells and that treatment with the Src family kinase inhibitor PP2 prevents Src activation and CTGF induction by TGF-beta1. Additionally, inhibiting Src activation prevented Erk activation, Smads 2 and 3 activation and nuclear translocation by TGF-beta1, demonstrating that Src is an essential upstream signaling partner of both Erk and Smads in osteoblasts. MAPKs such as Erk can modulate the Smad pathway directly by mediating the phosphorylation of Smads or indirectly through activation/inactivation of required nuclear co-activators that mediate Smad DNA binding. When we treated cells with the Erk inhibitor, PD98059, it inhibited TGF-beta1-induced CTGF protein expression but had no effect on Src activation, Smad activation or Smad nuclear translocation. However PD98059 impaired transcriptional complex formation on the Smad binding element (SBE) of the CTGF promoter, demonstrating that Erk activation was required for SBE transactivation. These data demonstrate that Src is an essential upstream signaling transducer of Erk and Smad signaling with respect to TGF-beta1 in osteoblasts and that Smads and Erk function independently but are both essential for forming a transcriptionally active complex on the CTGF promoter in osteoblasts.

  16. Balancing survival: the role of CTGF in controlling experience-modulated olfactory circuitry.

    PubMed

    Sharma, Tanu; Reed, Randall R

    2013-09-18

    The subventricular zone (SVZ) continuously supplies new interneurons that incorporate into pre-existing olfactory bulb circuitry. Khodosevich et al. (2013) show that connective tissue growth factor (CTGF) regulates a multicellular signaling cascade determining the number of postnatally born inhibitory interneurons in odor-activated glomeruli.

  17. Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.

    PubMed

    Ercan, Ebru; Han, Juliette M; Di Nardo, Alessia; Winden, Kellen; Han, Min-Joon; Hoyo, Leonie; Saffari, Afshin; Leask, Andrew; Geschwind, Daniel H; Sahin, Mustafa

    2017-03-06

    Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF). We characterize oligodendrocyte maturation both in vitro and in vivo. We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion that non-cell autonomously stunts oligodendrocyte development and decreases the total number of oligodendrocytes. Genetic deletion of CTGF from neurons, in turn, mitigates the TSC-dependent hypomyelination phenotype. These results show that the mechanistic target of rapamycin (mTOR) pathway in neurons regulates CTGF production and secretion, revealing a paracrine mechanism by which neuronal signaling regulates oligodendrocyte maturation and myelination in TSC. This study highlights the role of mTOR-dependent signaling between neuronal and nonneuronal cells in the regulation of myelin and identifies an additional therapeutic avenue for this disease.

  18. GPER in CAFs regulates hypoxia-driven breast cancer invasion in a CTGF-dependent manner.

    PubMed

    Ren, Juan; Guo, Hui; Wu, Huili; Tian, Tao; Dong, Danfeng; Zhang, Yuelang; Sui, Yanxia; Zhang, Yong; Zhao, Dongli; Wang, Shufeng; Li, Zongfang; Zhang, Xiaozhi; Liu, Rui; Qian, Jianshneg; Wei, Hongxia; Jiang, Wenjun; Liu, Ya; Li, Yi

    2015-04-01

    Recent advances indicate that cancer‑associated fibroblasts (CAFs) play a key role in cancer progression by contributing to invasion, metastasis and angiogenesis. Solid tumors often experience low oxygen tension environments, which induce gene expression changes and biological features leading to poor outcomes. The G-protein estrogen receptor (GPER) exhibits a stimulatory role in diverse types of cancer cells and in CAFs under hypoxic conditions. We investigated the role of CAFs and hypoxia in breast cancer aggressiveness, and examined the effect of GPER in CAFs on hypoxia-driven breast cancer progression. The results showed that hypoxia upregulated HIF-1α, GPER and α-SMA expression in CAFs, and induced the secretion of Interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) in CAFs. However, GPER silencing abrogated the above hypoxia-driven cytokine expression in CAFs. Moreover, knockdown of GPER in CAFs suppressed breast cancer cell invasion induced by CAF conditioned media (CM). Furthermore, GPER silencing in CAFs inhibited hypoxia-increased CTGF expression in CAFs and breast cancer cells cultured with CM from CAFs under hypoxic conditions. In addition, CTGF is responsible for the observed effects of GPER on CAFs activation and breast cancer invasion. Our findings further extend the molecular mechanisms through which the tumor microenvironment may contribute to cancer progression.

  19. Decorin alleviated chronic hydrocephalus via inhibiting TGF-β1/Smad/CTGF pathway after subarachnoid hemorrhage in rats.

    PubMed

    Yan, Hui; Chen, Yujie; Li, Lingyong; Jiang, Jiaode; Wu, Guangyong; Zuo, Yuchun; Zhang, John H; Feng, Hua; Yan, Xiaoxin; Liu, Fei

    2016-01-01

    Chronic hydrocephalus is one of the severe complications after subarachnoid hemorrhage (SAH). However, there is no efficient treatment for the prevention of chronic hydrocephalus, partially due to poor understanding of underlying pathogenesis, subarachnoid fibrosis. Transforming growth factor-β1(TGF-β1) is a potent fibrogenic factor implicated in wide range of fibrotic diseases. To investigate whether decorin, a natural antagonist for TGF-β1, protects against subarachnoid fibrosis and chronic hydrocephalus after SAH, two-hemorrhage-injection SAH model was conducted in 6-week-old rats. Recombinant human decorin(rhDecorin) (30ug/2ul) was administered before blood injection and on the 10th day after SAH. TGF-β1, p-Smad2/3, connective tissue growth factor (CTGF), collagen I and pro-collagen I c-terminal propeptide were assessed via western blotting, enzyme-linked immunosorbent assay, radioimmunoassay and immunofluorescence. And neurobehavioral tests and Morris water maze were employed to evaluate long-term neurological functions after SAH. We found that SAH induced heightened activation of TGF-β1/Smad/CTGF axis, presenting as a two peak response of TGF-β1 in cerebrospinal fluid, elevation of TGF-β1, p-Smad2/3, CTGF, collagen I in brain parenchyma and pro-collagen I c-terminal propeptide in cerebrospinal fluid, and increased lateral ventricle index. rhDecorin treatment effectively inhibited up-regulation of TGF-β1, p-Smad2/3, CTGF, collagen I and pro-collagen I c-terminal propeptide after SAH. Moreover, rhDecorin treatment significantly reduced lateral ventricular index and incidence of chronic hydrocephalus after SAH. Importantly, rhDecorin improved neurocognitive deficits after SAH. In conclusion, rhDecorin suppresses extracellular matrix accumulation and following subarachnoid fibrosis via inhibiting TGF-β1/Smad/CTGF pathway, preventing development of hydrocephalus and attenuating long-term neurocognitive defects after SAH.

  20. Connective tissue growth factor is required for skeletal development and postnatal skeletal homeostasis in male mice.

    PubMed

    Canalis, Ernesto; Zanotti, Stefano; Beamer, Wesley G; Economides, Aris N; Smerdel-Ramoya, Anna

    2010-08-01

    Connective tissue growth factor (CTGF), a member of the cysteine-rich 61 (Cyr 61), CTGF, nephroblastoma overexpressed (NOV) (CCN) family of proteins, is synthesized by osteoblasts, and its overexpression inhibits osteoblastogenesis and causes osteopenia. The global inactivation of Ctgf leads to defective endochondral bone formation and perinatal lethality; therefore, the consequences of Ctgf inactivation on the postnatal skeleton are not known. To study the function of CTGF, we generated Ctgf(+/LacZ) heterozygous null mice and tissue-specific null Ctgf mice by mating Ctgf conditional mice, where Ctgf is flanked by lox sequences with mice expressing the Cre recombinase under the control of the paired-related homeobox gene 1 (Prx1) enhancer (Prx1-Cre) or the osteocalcin promoter (Oc-Cre). Ctgf(+/LacZ) heterozygous mice exhibited transient osteopenia at 1 month of age secondary to decreased trabecular number. A similar osteopenic phenotype was observed in 1-month-old Ctgf conditional null male mice generated with Prx1-Cre, suggesting that the decreased trabecular number was secondary to impaired endochondral bone formation. In contrast, when the conditional deletion of Ctgf was achieved by Oc-Cre, an osteopenic phenotype was observed only in 6-month-old male mice. Osteoblast and osteoclast number, bone formation, and eroded surface were not affected in Ctgf heterozygous or conditional null mice. In conclusion, CTGF is necessary for normal skeletal development but to a lesser extent for postnatal skeletal homeostasis.

  1. Angiotensin II increases CTGF expression via MAPKs/TGF-{beta}1/TRAF6 pathway in atrial fibroblasts

    SciTech Connect

    Gu, Jun; Liu, Xu; Wang, Quan-xing; Tan, Hong-wei; Guo, Meng; Jiang, Wei-feng; Zhou, Li

    2012-10-01

    The activation of transforming growth factor-{beta}1(TGF-{beta}1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGF{beta}1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGF{beta}-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-{beta}1/non-Smad signaling pathways. In the present study, we explored the role of TGF-{beta}1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 {mu}M) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 {mu}M) also promoted TGF{beta}1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGF{beta}1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGF{beta}1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis. -- Highlights: Black-Right-Pointing-Pointer MAPKs/TGF{beta}1/TRAF6 participates in AngII-induced CTGF expression in atrial fibroblasts. Black-Right-Pointing-Pointer TGF{beta}1/TRAF6 participates in AngII-induced atrial fibroblasts proliferation. Black-Right-Pointing-Pointer TRAF6 may represent a new target for reversing Ang II-induced atrial fibrosis.

  2. Angiotensin II Enhances Connecting Tubule Glomerular Feedback (CTGF)

    PubMed Central

    Ren, YiLin; D’Ambrosio, Martin A.; Garvin, Jeffrey L.; Carretero, Oscar A.

    2011-01-01

    Increasing Na delivery to epithelial Na channels (ENaC) in the connecting tubule (CNT) causes dilation of the afferent arteriole (Af-Art), a process we call CNT glomerular feedback (CTGF). Angiotensin II (Ang II) stimulates ENaC in the collecting duct via AT1 receptors. We hypothesized that Ang II in the CNT lumen enhances CTGF by activation of AT1 receptors, protein kinase C (PKC) and ENaC. Rabbit Af-Arts and their adherent CNT were microperfused and preconstricted with norepinephrine. Each experiment involved generating two consecutive concentration-response curves by increasing NaCl in the CNT lumen. During the control period, the maximum dilation of the Af-Art was 7.9 ± 0.4 μm, and the concentration of NaCl in the CNT needed to achieve half maximal response (EC50) was 34.7 ± 5.2 mmol/L. After adding Ang II (10−9 mol/L) to the CNT lumen, the maximal response was 9.5 ± 0.7 μm and the EC50 was 11.6 ± 1.3 mmol/L (P=0.01 vs. control). Losartan, an AT1 antagonist (10−6 mol/L) blocked the stimulatory effect of Ang II, PD123319, an AT2 antagonist (10−6 mol/L) did not. The PKC inhibitor staurosporine (10−8 mol/L) added to the CNT inhibited the stimulatory effect of Ang II. The ENaC inhibitor benzamil (10−6 mol/L) prevented both CTGF and its stimulation by Ang II. We concluded that Ang II in the CNT lumen enhances CTGF via activation of AT1, and that this effect requires activation of PKC and ENaC. Potentiation of CTGF by Ang II could help preserve glomerular filtration rate in the presence of renal vasoconstriction. PMID:20696981

  3. PLGA-PEG-PLGA microspheres as a delivery vehicle for antisense oligonucleotides to CTGF: Implications on post-surgical peritoneal adhesion prevention

    NASA Astrophysics Data System (ADS)

    Azeke, John Imuetinyan-Jesu, Jr.

    Abdominal adhesions are the aberrant result of peritoneal wound healing commonly associated with surgery and inflammation. A subject of a large number of studies since the first half of the last century, peritoneal adhesion prevention has, for the most part, evaded the scientific community and continues to cost Americans an estimated $2-4 billion annually. It is known that transforming growth factor-beta (TGF-beta) plays a key role in the wound healing cascade; however, suppression of this multifunctional growth factor's activity may have more harmful consequences than can be tolerated. As a result, much attention has fallen on connective tissue growth factor (CTGF), a downstream mediator of TGF-beta's fibrotic action. It has been demonstrated in several in vitro models, that the suppression of CTGF hinders fibroblast proliferation, a necessary condition for fibrosis. Furthermore, antisense oligonucleotides (antisense oligos, AO) to CTGF have been shown to knock down CTGF mRNA levels by specifically hindering the translation of CTGF protein. Antisense technologies have met with a great deal of excitement as a viable means of preventing diseases such as adhesions by hindering protein translation at the mRNA level. However, the great challenge associated with the use of these drugs lies in the short circulation time when administered "naked". Viral delivery systems, although excellent platforms in metabolic studies, are not ideal for diagnostic use because of the inherent danger associated with viral vectors. Microparticles made of biodegradable polymers have therefore presented themselves as a viable means of delivering these drugs to target cells over extended periods. Herein, we present two in vivo studies confirming the up-regulation of TGF-beta protein and CTGF mRNA following injury to the uterine tissues of female rats. We were able to selectively knockdown post-operative CTGF protein levels following surgery, however, our observations led us to conclude that

  4. Age-dependent shifts in renal response to injury relate to altered BMP6/CTGF expression and signaling.

    PubMed

    Falke, Lucas L; Kinashi, Hiroshi; Dendooven, Amelie; Broekhuizen, Roel; Stoop, Reinout; Joles, Jaap A; Nguyen, Tri Q; Goldschmeding, Roel

    2016-11-01

    Age is associated with an increased prevalence of chronic kidney disease (CKD), which, through progressive tissue damage and fibrosis, ultimately leads to loss of kidney function. Although much effort is put into studying CKD development experimentally, age has rarely been taken into account. Therefore, we investigated the effect of age on the development of renal tissue damage and fibrosis in a mouse model of obstructive nephropathy (i.e., unilateral ureter obstruction; UUO). We observed that after 14 days, obstructed kidneys of old mice had more tubulointerstitial atrophic damage but less fibrosis than those of young mice. This was associated with reduced connective tissue growth factor (CTGF), and higher bone morphogenetic protein 6 (BMP6) expression and pSMAD1/5/8 signaling, while transforming growth factor-β expression and transcriptional activity were no different in obstructed kidneys of old and young mice. In vitro, CTGF bound to and inhibited BMP6 activity. In summary, our data suggest that in obstructive nephropathy atrophy increases and fibrosis decreases with age and that this relates to increased BMP signaling, most likely due to higher BMP6 and lower CTGF expression.

  5. Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns.

    PubMed

    Castleberry, Steven A; Golberg, Alexander; Sharkh, Malak Abu; Khan, Saiqa; Almquist, Benjamin D; Austen, William G; Yarmush, Martin L; Hammond, Paula T

    2016-07-01

    Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFβ pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research.

  6. Connective tissue growth factor is overexpressed in muscles of human muscular dystrophy.

    PubMed

    Sun, Guilian; Haginoya, Kazuhiro; Wu, Yanling; Chiba, Yoko; Nakanishi, Tohru; Onuma, Akira; Sato, Yuko; Takigawa, Masaharu; Iinuma, Kazuie; Tsuchiya, Shigeru

    2008-04-15

    The detailed process of how dystrophic muscles are replaced by fibrotic tissues is unknown. In the present study, the immunolocalization and mRNA expression of connective tissue growth factor (CTGF) in muscles from normal and dystrophic human muscles were examined with the goal of elucidating the pathophysiological function of CTGF in muscular dystrophy. Biopsies of frozen muscle from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, congenital muscular dystrophy, spinal muscular atrophy, congenital myopathy were analyzed using anti-CTGF polyclonal antibody. Reverse transcription-polymerase chain reaction (RT-PCR) was also performed to evaluate the expression of CTGF mRNA in dystrophic muscles. In normal muscle, neuromuscular junctions and vessels were CTGF-immunopositive, which suggests a physiological role for CTGF in these sites. In dystrophic muscle, CTGF immunoreactivity was localized to muscle fiber basal lamina, regenerating fibers, and the interstitium. Triple immunolabeling revealed that activated fibroblasts were immunopositive for CTGF and transforming growth factor-beta1 (TGF-beta1). RT-PCR analysis revealed increased levels of CTGF mRNA in the muscles of DMD patients. Co-localization of TGF-beta1 and CTGF in activated fibroblasts suggests that CTGF expression is regulated by TGF-beta1 through a paracrine/autocrine mechanism. In conclusion, TGF-beta1-CTGF pathway may play a role in the fibrosis that is commonly observed in muscular dystrophy.

  7. Differential expression of CCN family members CYR611, CTGF and NOV in gastric cancer and their association with disease progression

    PubMed Central

    Li, Jun; Gao, Xiangyu; Ji, Ke; Sanders, Andrew J.; Zhang, Zhongtao; Jiang, Wen G.; Ji, Jiafu; Ye, Lin

    2016-01-01

    CCN is an acronym for cysteine-rich protein 61 (CYR61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed (NOV). Aberrations of certain CCN members including CYR61, CTGF, Wnt1-inducible signalling pathway protein (WISP)-1 and -3 have been reported in gastric cancer. The present study aimed to examine the clinical relevance of NOV along with CYR61 and CTGF in gastric cancer by analysing their transcript levels. CYR61, CTGF and NOV transcript expression in 324 gastric cancer samples with paired adjacent normal gastric tissues were determined using real-time quantitative PCR and the results were statistically analysed against patient clinicopathological data using SPSS software. NOV mRNA levels in gastric cancer tissues were significantly elevated when compared with levels in their paired adjacent non-cancerous tissues. Local advanced tumours with invasive expansion (T3 and T4) expressed higher levels of NOV (p=0.013) compared with the less invasive tumours (T1 and T2). CYR61 transcript levels were also significantly increased in gastric cancers compared with levels in the adjacent non-cancerous tissues. Kaplan-Meier survival curves revealed that patients with CYR61-low transcript levels had longer overall survival (OS) (p=0.018) and disease-free survival (DFS) (p=0.015). NOV overexpression promoted the in vitro proliferation of AGS cells while the knockdown resulted in a reduced proliferation of HGC27 cells. A similar effect was observed for the invasion of these two gastric cancer cell lines. NOV expression was increased in gastric cancer which was associated with local invasion and distant metastases. Taken together, the expression of NOV and CYR61 was increased in gastric cancer. The elevated expression of CYR61 was associated with poorer survival. NOV promoted proliferation and invasion of gastric cancer cells. Further investigations may highlight their predictive and therapeutic potential in gastric cancer. PMID:27633176

  8. Genetic Analysis of Connective Tissue Growth Factor as an Effector of Transforming Growth Factor β Signaling and Cardiac Remodeling

    PubMed Central

    Accornero, Federica; van Berlo, Jop H.; Correll, Robert N.; Elrod, John W.; Sargent, Michelle A.; York, Allen; Rabinowitz, Joseph E.; Leask, Andrew

    2015-01-01

    The matricellular secreted protein connective tissue growth factor (CTGF) is upregulated in response to cardiac injury or with transforming growth factor β (TGF-β) stimulation, where it has been suggested to function as a fibrotic effector. Here we generated transgenic mice with inducible heart-specific CTGF overexpression, mice with heart-specific expression of an activated TGF-β mutant protein, mice with heart-specific deletion of Ctgf, and mice in which Ctgf was also deleted from fibroblasts in the heart. Remarkably, neither gain nor loss of CTGF in the heart affected cardiac pathology and propensity toward early lethality due to TGF-β overactivation in the heart. Also, neither heart-specific Ctgf deletion nor CTGF overexpression altered cardiac remodeling and function with aging or after multiple acute stress stimuli. Cardiac fibrosis was also unchanged by modulation of CTGF levels in the heart with aging, pressure overload, agonist infusion, or TGF-β overexpression. However, CTGF mildly altered the overall cardiac response to TGF-β when pressure overload stimulation was applied. CTGF has been proposed to function as a critical TGF-β effector in underlying tissue remodeling and fibrosis throughout the body, although our results suggest that CTGF is of minimal importance and is an unlikely therapeutic vantage point for the heart. PMID:25870108

  9. Cell Permeant Peptide Analogues of the Small Heat Shock Protein, HSP20, Reduce TGF-β1-Induced CTGF Expression in Keloid Fibroblasts

    PubMed Central

    Lopes, Luciana B.; Furnish, Elizabeth J.; Komalavilas, Padmini; Flynn, Charles R.; Ashby, Patricia; Hansen, Adam; Ly, Daphne P.; Yang, George P.; Longaker, Michael T.; Panitch, Alyssa; Brophy, Colleen M.

    2009-01-01

    A growing body of evidence suggests the involvement of connective tissue growth factor (CTGF) in the development and maintenance of fibrosis and excessive scarring. As the expression of this protein requires an intact actin cytoskeleton, disruption of the cytoskeleton represents an attractive strategy to decrease CTGF expression and, consequently, excessive scarring. The small heat-shock-related protein (HSP20), when phosphorylated by cyclic nucleotide signaling cascades, displaces phospho-cofilin from the 14-3-3 scaffolding protein leading to activation of cofilin as an actin-depolymerizing protein. In the present study, we evaluated the effect of AZX100, a phosphopeptide analogue of HSP20, on transforming growth factor-β-1 (TGF-β1)-induced CTGF and collagen expression in human keloid fibroblasts. We also examined the effect of AZX100 on scar formation in vivo in dermal wounds in a Siberian hamster model. AZX100 decreased the expression of CTGF and type I collagen induced by TGF-β1, endothelin, and lysophosphatidic acid. Treatment with AZX100 decreased stress fiber formation and altered the morphology of human dermal keloid fibroblasts. In vivo, AZX100 significantly improved collagen organization in a Siberian hamster scarring model. Taken together, these results suggest the potential use of AZX100 as a strategy to prevent excessive scarring and fibrotic disorders. PMID:18787533

  10. Caffeine and rolipram affect Smad signalling and TGF-β1 stimulated CTGF and transgelin expression in lung epithelial cells.

    PubMed

    Fehrholz, Markus; Speer, Christian P; Kunzmann, Steffen

    2014-01-01

    Caffeine administration is an important part of the therapeutic treatment of bronchopulmonary dysplasia (BPD) in preterm infants. However, caffeine mediated effects on airway remodelling are still undefined. The TGF-β/Smad signalling pathway is one of the key pathways involved in airway remodelling. Connective tissue growth factor (CTGF), a downstream mediator of TGF-β, and transgelin, a binding and stabilising protein of the cytoskeleton, are both regulated by TGF-β1 and play an important role in airway remodelling. Both have also been implicated in the pathogenesis of BPD. The aim of the present study was to clarify whether caffeine, an unspecific phosphodiesterase (PDE) inhibitor, and rolipram, a prototypical PDE-4 selective inhibitor, were both able to affect TGF-β1-induced Smad signalling and CTGF/transgelin expression in lung epithelial cells. Furthermore, the effect of transgelin knock-down on Smad signalling was studied. The pharmacological effect of caffeine and rolipram on Smad signalling was investigated by means of a luciferase assay via transfection of a TGF-β1-inducible reporter plasmid in A549 cells. The regulation of CTGF and transgelin expression by caffeine and rolipram were studied by promoter analysis, real-time PCR and Western blot. Endogenous transgelin expression was down-regulated by lentiviral transduction mediating transgelin-specific shRNA expression. The addition of caffeine and rolipram inhibited TGF-β1 induced reporter gene activity in a concentration-related manner. They also antagonized the TGF-β1 induced up-regulation of CTGF and transgelin on the promoter-, the mRNA-, and the protein-level. Functional analysis showed that transgelin silencing reduced TGF-β1 induced Smad-signalling and CTGF induction in lung epithelial cells. The present study highlights possible new molecular mechanisms of caffeine and rolipram including an inhibition of Smad signalling and of TGF-β1 regulated genes involved in airway remodelling. An

  11. Development of a novel gene silencer pyrrole-imidazole polyamide targeting human connective tissue growth factor.

    PubMed

    Wan, Jian-Xin; Fukuda, Noboru; Ueno, Takahiro; Watanabe, Takayoshi; Matsuda, Hiroyuki; Saito, Kosuke; Nagase, Hiroki; Matsumoto, Yoshiaki; Matsumoto, Koichi

    2011-01-01

    Pyrrole-imidazole (PI) polyamide can bind to specific sequences in the minor groove of double-helical DNA and inhibit transcription of the genes. We designed and synthesized a PI polyamide to target the human connective tissue growth factor (hCTGF) promoter region adjacent to the Smads binding site. Among coupling activators that yield PI polyamides, 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU) was most effective in total yields of PI polyamides. A gel shift assay showed that a PI polyamide designed specifically for hCTGF (PI polyamide to hCTGF) bound the appropriate double-stranded oligonucleotide. A fluorescein isothiocyanate (FITC)-conjugated PI polyamide to CTGF permeated cell membranes and accumulated in the nuclei of cultured human mesangial cells (HMCs) and remained there for 48 h. The PI polyamide to hCTGF significantly decreased phorbol 12-myristate acetate (PMA)- or transforming growth factor-β1 (TGF-β1)-stimulated luciferase activity of the hCTGF promoter in cultured HMCs. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated expression of hCTGF mRNA in a dose-dependent manner. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated levels of hCTGF protein in HMCs. These results indicate that the developed synthetic PI polyamide to hCTGF could be a novel gene silencer for fibrotic diseases.

  12. Expression of TGF-β1 and CTGF Is Associated with Fibrosis of Denervated Sternocleidomastoid Muscles in Mice.

    PubMed

    Liu, Fei; Tang, Weifang; Chen, Donghui; Li, Meng; Gao, Yinna; Zheng, Hongliang; Chen, Shicai

    2016-01-01

    Injury to the recurrent laryngeal nerve often leads to permanent vocal cord paralysis, which has a significant negative impact on the quality of life. Long-term denervation can induce laryngeal muscle fibrosis, which obstructs the muscle recovery after laryngeal reinnervation. However, the mechanisms of fibrosis remain unclear. In this study, we aimed to analyze the changes in the expression of fibrosis-related factors, including transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) in denervated skeletal muscles using a mouse model of accessory nerve transection. Because of the small size, we used sternocleidomastoid muscles instead of laryngeal muscles for denervation experiments. Masson's trichrome staining showed that the grade of atrophy and fibrosis of muscles became more severe with time, but showed a plateau at 4 weeks after denervation, followed by a slow decrease. Quantitative assessment and immunohistochemistry showed that TGF-β1 expression peaked at 1 week after denervation (p < 0.05) and was maintained at its high level until 4 weeks. CTGF- and α-SMA-positive muscle cells were detected at 1 week after denervation, peaked at 2 weeks (p < 0.05), and remained at high levels with a subsequent slight decrease for 3-4 weeks. These results suggest that TGF-β1 and CTGF may be involved in the process of denervated skeletal muscle fibrosis. They may induce the differentiation of myoblasts into myofibroblasts, as characterized by the activation of α-SMA. These findings may provide insights on key pathological processes in denervated skeletal muscle fibrosis and develop novel therapeutic strategies.

  13. Connective tissue growth factor is a substrate of ADAM28

    SciTech Connect

    Mochizuki, Satsuki; Tanaka, Rena; Shimoda, Masayuki; Onuma, Junko; Fujii, Yutaka; Jinno, Hiromitsu; Okada, Yasunori

    2010-11-26

    Research highlights: {yields} The hyper-variable region in the cysteine-rich domain of ADAM28 binds to C-terminal domain of CTGF. {yields} ADAM28 cleaves CTGF alone and CTGF in the CTGF/VEGF{sub 165} complex. {yields} CTGF digestion by ADAM28 releases biologically active VEGF{sub 165} from the complex. {yields} ADAM28, CTGF and VEGF{sub 165} are commonly co-expressed by carcinoma cells in human breast carcinoma tissues. {yields} These suggest that ADAM28 promotes VEGF{sub 165}-induced angiogenesis in the breast carcinomas by selective CTGF digestion in the CTGF/VEGF{sub 165} complex. -- Abstract: ADAM28, a member of the ADAM (a disintegrin and metalloproteinase) gene family, is over-expressed by carcinoma cells and the expression correlates with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, information about substrates of ADAM28 is limited. We screened interacting molecules of ADAM28 in human lung cDNA library by yeast two-hybrid system and identified connective tissue growth factor (CTGF). Binding of CTGF to proADAM28 was demonstrated by yeast two-hybrid assay and protein binding assay. ADAM28 cleaved CTGF in dose- and time-dependent manners at the Ala{sup 181}-Tyr{sup 182} and Asp{sup 191}-Pro{sup 192} bonds in the hinge region of the molecule. ADAM28 selectively digested CTGF in the complex of CTGF and vascular endothelial growth factor{sub 165} (VEGF{sub 165}), releasing biologically active VEGF{sub 165} from the complex. RT-PCR and immunohistochemical analyses demonstrated that ADAM28, CTGF and VEGF are commonly co-expressed in the breast carcinoma tissues. These data provide the first evidence that CTGF is a novel substrate of ADAM28 and suggest that ADAM28 may promote VEGF{sub 165}-induced angiogenesis in the breast carcinomas by the CTGF digestion in the CTGF/VEGF{sub 165} complex.

  14. Role of CTGF in sensitivity to hyperthermia in ovarian and uterine cancers

    PubMed Central

    Hatakeyama, Hiroto; Wu, Sherry Y.; Lyons, Yasmin A.; Pradeep, Sunila; Wang, Wanqin; Huang, Qian; Court, Karem A.; Liu, Tao; Nie, Song; Rodriguez-Aguayo, Cristian; Shen, Fangrong; Huang, Yan; Hisamatsu, Takeshi; Mitamura, Takashi; Jennings, Nicholas; Shim, Jeajun; Dorniak, Piotr L.; Mangala, Lingegowda S.; Petrillo, Marco; Petyuk, Vladislav A.; Schepmoes, Athena A.; Shukla, Anil K.; Torres-Lugo, Madeline; Lee, Ju-Seog; Rodland, Karin D.; Fagotti, Anna; Lopez-Berestein, Gabriel; Li, Chun; Sood, Anil K.

    2016-01-01

    Summary Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits of and predictors of sensitivity of cancer to hyperthermia are poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures in and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF siRNA treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia resistant cancers. PMID:27806300

  15. Role of CTGF in sensitivity to hyperthermia in ovarian and uterine cancers

    SciTech Connect

    Hatakeyama, Hiroto; Wu, Sherry Y.; Lyons, Yasmin A.; Pradeep, Sunila; Wang, Wanqin; Huang, Qian; Court, Karem A.; Liu, Tao; Nie, Song; Rodriguez-Aguayo, Cristian; Shen, Fangrong; Huang, Yan; Hisamatsu, Takeshi; Mitamura, Takashi; Jennings, Nicholas; Shim, Jeajun; Dorniak, Piotr L.; Mangala, Lingegowda S.; Petrillo, Marco; Petyuk, Vladislav A.; Schepmoes, Athena A.; Shukla, Anil K.; Torres-Lugo, Madeline; Lee, Ju -Seog; Rodland, Karin D.; Fagotti, Anna; Lopez-Berestein, Gabriel; Li, Chun; Sood, Anil K.

    2016-11-01

    Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. Lastly, CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.

  16. Role of CTGF in sensitivity to hyperthermia in ovarian and uterine cancers

    DOE PAGES

    Hatakeyama, Hiroto; Wu, Sherry Y.; Lyons, Yasmin A.; ...

    2016-11-01

    Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. Lastly, CTGF silencingmore » aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.« less

  17. Connective tissue growth factor and its regulation: a new element in diabetic glomerulosclerosis.

    PubMed

    Riser, B L; Cortes, P

    2001-01-01

    Connective tissue growth factor (CTGF), a member of the closely related CCN family of cytokines appears to be fibrotic in skin. To determine whether CTGF is implicated in diabetic glomerulosclerosis we studied cultured rat mesangial cells (MC) as well as kidney cortex and microdissected glomeruli from obese, diabetic db/db mice and their normal counterparts. Exposure of MC to rhCTGF significantly increased fibronectin and collagen type I secretion. Further, unstimulated MC expressed low levels of CTGF message and secreted minimal amounts of CTGF protein (36-38 kDa). However, exposure to TGF-beta, increased glucose concentrations, or cyclic mechanical strain, all causal factors in glomerulosclerosis, markedly induced the expression of CTGF transcripts. With all but mechanical strain there was a concomitant stimulation of CTGF protein secretion. TGF-beta also induced abundant quantities of a small molecular weight form of CTGF (18 kDa). The induction of CTGF protein by a high glucose concentration was mediated by TGF-beta, since a TGF-beta neutralizing antibody blocked this stimulation. In vivo studies using quantitative RT-PCR demonstrated that while CTGF transcripts were low in the glomeruli of control mice, expression was increased 27-fold after approximately 3.5 months of diabetes. These changes occurred early in diabetic nephropathy when mesangial expansion was mild, and interstitial disease and proteinuria were absent. A substantially reduced elevation of CTGF mRNA (2-fold) observed in whole kidney cortices indicted that the primary alteration of CTGF expression was in the glomerulus. These results suggest that CTGF upregulation is an important factor in the pathogenesis of mesangial matrix accumulation in both diabetic and non-diabetic glomerulosclerosis, acting downstream of TGF-beta.

  18. Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

    SciTech Connect

    Hayata, Nozomi; Fujio, Yasushi; Yamamoto, Yasuhiro; Iwakura, Tomohiko; Obana, Masanori; Takai, Mika; Mohri, Tomomi; Nonen, Shinpei; Maeda, Makiko; Azuma, Junichi

    2008-05-30

    In the process of cardiac remodeling, connective tissue growth factor (CTGF/CCN2) is secreted from cardiac myocytes. Though CTGF is well known to promote fibroblast proliferation, its pathophysiological effects in cardiac myocytes remain to be elucidated. In this study, we examined the biological effects of CTGF in rat neonatal cardiomyocytes. Cardiac myocytes stimulated with full length CTGF and its C-terminal region peptide showed the increase in cell surface area. Similar to hypertrophic ligands for G-protein coupled receptors, such as endothelin-1, CTGF activated amino acid uptake; however, CTGF-induced hypertrophy is not associated with the increased expression of skeletal actin or BNP, analyzed by Northern-blotting. CTGF treatment activated ERK1/2, p38 MAPK, JNK and Akt. The inhibition of Akt by transducing dominant-negative Akt abrogated CTGF-mediated increase in cell size, while the inhibition of MAP kinases did not affect the cardiac hypertrophy. These findings indicate that CTGF is a novel hypertrophic factor in cardiac myocytes.

  19. Connective tissue growth factor expression and Smad signaling during mouse heart development and myocardial infarction.

    PubMed

    Chuva de Sousa Lopes, Susana M; Feijen, Alie; Korving, Jeroen; Korchynskyi, Olexander; Larsson, Jonas; Karlsson, Stefan; ten Dijke, Peter; Lyons, Karen M; Goldschmeding, Roel; Doevendans, Pieter; Mummery, Christine L

    2004-11-01

    Connective tissue growth factor (CTGF) is reported to be a target gene of transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) in vitro. Its physiological role in angiogenesis and skeletogenesis during mouse development has been described recently. Here, we have mapped expression of CTGF mRNA during mouse heart development, postnatal adult life, and after experimental myocardial infarction. Furthermore, we investigated the relationship between CTGF and the BMP/TGFbeta signaling pathway in particular during heart development in mutant mice. Postnatally, CTGF expression in the heart became restricted to the atrium. Strikingly, 1 week after myocardial infarction, when myocytes have disappeared from the infarct zone, CTGF and TGFbeta expression as well as activated forms of TGFbeta but not BMP, Smad effector proteins are colocalized exclusively in the fibroblasts of the scar tissue, suggesting possible cooperation between CTGF and TGFbeta during the pathological fibrotic response.

  20. Expression and clinical significance of connective tissue growth factor in advanced head and neck squamous cell cancer.

    PubMed

    Kikuchi, Ryoko; Kikuchi, Yoshihiro; Tsuda, Hitoshi; Maekawa, Hitoshi; Kozaki, Ken-Ichi; Imoto, Issei; Tamai, Seiichi; Shiotani, Akihiro; Iwaya, Keiichi; Sakamoto, Masaru; Sekiya, Takao; Matsubara, Osamu

    2014-07-01

    Connective tissue growth factor (CTGF) has been reported to play critical roles in the tumorigenesis of several human malignancies. This study was performed to evaluate CTGF protein expression in head and neck squamous cell carcinoma (HNSCC). Surgical specimens from 76 primary HNSCC were obtained with written informed consents and the expression level of CTGF was immunohistochemically evaluated. The cytoplasmic immunoreactivity of CTGF in cancer cells was semiquantitatively classified into low and high expression. Among all 76 cases with or without neoadjuvant therapy, low CTGF showed significantly longer (P = 0.0282) overall survival (OS), but not disease-free survival (DFS) than high CTGF. Although low CTGF in patients with stage I, II and III did not result in any significant difference of the OS and DFS, stage IV HNSCC patients with low CTGF showed significantly longer OS (P = 0.032) and DFS (P = 0.0107) than those with high CTGF. These differences in stage IV cases were also confirmed using multivariate analyses. These results suggest that low CTGF in stage IV HNSCC is an independent prognostic factor, despite with or without neoadjuvant therapy.

  1. Matricellular proteins of the Cyr61/CTGF/NOV (CCN) family and the nervous system

    PubMed Central

    Malik, Anna R.; Liszewska, Ewa; Jaworski, Jacek

    2015-01-01

    Matricellular proteins are secreted proteins that exist at the border of cells and the extracellular matrix (ECM). However, instead of playing a role in structural integrity of the ECM, these proteins, that act as modulators of various surface receptors, have a regulatory function and instruct a multitude of cellular responses. Among matricellular proteins are members of the Cyr61/CTGF/NOV (CCN) protein family. These proteins exert their activity by binding directly to integrins and heparan sulfate proteoglycans and activating multiple intracellular signaling pathways. CCN proteins also influence the activity of growth factors and cytokines and integrate their activity with integrin signaling. At the cellular level, CCN proteins regulate gene expression and cell survival, proliferation, differentiation, senescence, adhesion, and migration. To date, CCN proteins have been extensively studied in the context of osteo- and chondrogenesis, angiogenesis, and carcinogenesis, but the expression of these proteins is also observed in a variety of tissues. The role of CCN proteins in the nervous system has not been systematically studied or described. Thus, the major aim of this review is to introduce the CCN protein family to the neuroscience community. We first discuss the structure, interactions, and cellular functions of CCN proteins and then provide a detailed review of the available data on the neuronal expression and contribution of CCN proteins to nervous system development, function, and pathology. PMID:26157362

  2. FoxO proteins mediate hypoxic induction of connective tissue growth factor in endothelial cells.

    PubMed

    Samarin, Jana; Wessel, Julia; Cicha, Iwona; Kroening, Sven; Warnecke, Christina; Goppelt-Struebe, Margarete

    2010-02-12

    Hypoxia, a driving force in neovascularization, promotes alterations in gene expression mediated by hypoxia-inducible factor (HIF)-1alpha. Connective tissue growth factor (CTGF, CCN2) is a modulator of endothelial cell growth and migration, but its regulation by hypoxia is poorly understood. Therefore, we analyzed signaling pathways involved in the regulation of CTGF by hypoxia in endothelial cells. Exposure to low oxygen tension or treatment with the hypoxia-mimetic dimethyloxalyl glycine (DMOG) stabilized HIF-1alpha and up-regulated CTGF in human umbilical vein endothelial cells and in a murine microvascular endothelial cell line. Induction of CTGF correlated with a HIF-dependent increase in protein and mRNA levels, and nuclear accumulation of the transcription factor FoxO3a. By contrast, gene expression and cellular localization of FoxO1 were not significantly altered by hypoxia. Expression of CTGF was strongly reduced by siRNA silencing of FoxO1 or FoxO3a. Furthermore, nuclear exclusion of FoxO1/3a transcription factors by inhibition of serine/threonine protein phosphatases by okadaic acid inhibited CTGF expression, providing evidence for both FoxO proteins as regulators of CTGF expression. The DMOG-stimulated induction of CTGF was further increased when endothelial cells were co-incubated with transforming growth factor-beta, an activator of Smad signaling. Activation of RhoA-Rho kinase signaling by the microtubule-disrupting drug combretastatin A4 also enhanced the DMOG-induced CTGF expression, thus placing CTGF induction by hypoxia in a network of interacting signaling pathways. Our findings provide evidence that FoxO1, hypoxia-stimulated expression of FoxO3a and its nuclear accumulation are required for the induction of CTGF by hypoxia in endothelial cells.

  3. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis.

    PubMed

    Riser, B L; Denichilo, M; Cortes, P; Baker, C; Grondin, J M; Yee, J; Narins, R G

    2000-01-01

    Connective tissue growth factor (CTGF) is a peptide secreted by cultured endothelial cells and fibroblasts when stimulated by transforming growth factor-beta (TGF-beta), and is overexpressed during fibrotic processes in coronary arteries and in skin. To determine whether CTGF is implicated in the pathogenesis of diabetic glomerulosclerosis, cultured rat mesangial cells (MC) as well as kidney cortex and microdissected glomeruli were examined from obese, diabetic db/db mice and their normal counterparts. Exposure of MC to recombinant human CTGF significantly increased fibronectin and collagen type I production. Furthermore, unstimulated MC expressed low levels of CTGF message and secreted minimal amounts of CTGF protein (36 to 38 kD) into the media. However, sodium heparin treatment resulted in a greater than fourfold increase in media-associated CTGF, suggesting that the majority of CTGF produced was cell- or matrix-bound. Exposure of MC to TGF-beta, increased glucose concentrations, or cyclic mechanical strain, all causal factors in diabetic glomerulosclerosis, markedly induced the expression of CTGF transcripts, while recombinant human CTGF was able to autoinduce its own expression. TGF-, and high glucose, but not mechanical strain, stimulated the concomitant secretion of CTGF protein, the former also inducing abundant quantities of a small molecular weight form of CTGF (18 kD) containing the heparin-binding domain. The induction of CTGF protein by a high glucose concentration was mediated by TGF-beta, since a TGF-beta-neutralizing antibody blocked this stimulation. In vivo studies using quantitative reverse transcription-PCR demonstrated that although CTGF transcripts were low in the glomeruli of control mice, expression was increased 28-fold after approximately 3.5 mo of diabetes. This change occurred early in the course of diabetic nephropathy when mesangial expansion was mild, and interstitial disease and proteinuria were absent. A substantially reduced

  4. Connective tissue growth factor inhibition attenuates left ventricular remodeling and dysfunction in pressure overload-induced heart failure.

    PubMed

    Szabó, Zoltán; Magga, Johanna; Alakoski, Tarja; Ulvila, Johanna; Piuhola, Jarkko; Vainio, Laura; Kivirikko, Kari I; Vuolteenaho, Olli; Ruskoaho, Heikki; Lipson, Kenneth E; Signore, Pierre; Kerkelä, Risto

    2014-06-01

    Connective tissue growth factor (CTGF) is involved in the pathogenesis of various fibrotic disorders. However, its role in the heart is not clear. To investigate the role of CTGF in regulating the development of cardiac fibrosis and heart failure, we subjected mice to thoracic aortic constriction (TAC) or angiotensin II infusion, and antagonized the function of CTGF with CTGF monoclonal antibody (mAb). After 8 weeks of TAC, mice treated with CTGF mAb had significantly better preserved left ventricular (LV) systolic function and reduced LV dilatation compared with mice treated with control immunoglobulin G. CTGF mAb-treated mice exhibited significantly smaller cardiomyocyte cross-sectional area and reduced expression of hypertrophic marker genes. CTGF mAb treatment reduced the TAC-induced production of collagen 1 but did not significantly attenuate TAC-induced accumulation of interstitial fibrosis. Analysis of genes regulating extracellular matrix proteolysis showed decreased expression of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 in mice treated with CTGF mAb. In contrast to TAC, antagonizing the function of CTGF had no effect on LV dysfunction or LV hypertrophy in mice subjected to 4-week angiotensin II infusion. Further analysis showed that angiotensin II-induced expression of hypertrophic marker genes or collagens was not affected by treatment with CTGF mAb. In conclusion, CTGF mAb protects from adverse LV remodeling and LV dysfunction in hearts subjected to pressure overload by TAC. Antagonizing the function of CTGF may offer protection from cardiac end-organ damage in patients with hypertension.

  5. Connective Tissue Growth Factor reporter mice label a subpopulation of mesenchymal progenitor cells that reside in the trabecular bone region.

    PubMed

    Wang, Wen; Strecker, Sara; Liu, Yaling; Wang, Liping; Assanah, Fayekah; Smith, Spenser; Maye, Peter

    2015-02-01

    Few gene markers selectively identify mesenchymal progenitor cells inside the bone marrow. We have investigated a cell population located in the mouse bone marrow labeled by Connective Tissue Growth Factor reporter expression (CTGF-EGFP). Bone marrow flushed from CTGF reporter mice yielded an EGFP+ stromal cell population. Interestingly, the percentage of stromal cells retaining CTGF reporter expression decreased with age in vivo and was half the frequency in females compared to males. In culture, CTGF reporter expression and endogenous CTGF expression marked the same cell types as those labeled using Twist2-Cre and Osterix-Cre fate mapping approaches, which previously had been shown to identify mesenchymal progenitors in vitro. Consistent with this past work, sorted CTGF+ cells displayed an ability to differentiate into osteoblasts, chondrocytes, and adipocytes in vitro and into osteoblast, adipocyte, and stromal cell lineages after transplantation into a parietal bone defect. In vivo examination of CTGF reporter expression in bone tissue sections revealed that it marked cells highly localized to the trabecular bone region and was not expressed in the perichondrium or periosteum. Mesenchymal cells retaining high CTGF reporter expression were adjacent to, but distinct from mature osteoblasts lining bone surfaces and endothelial cells forming the vascular sinuses. Comparison of CTGF and Osterix reporter expression in bone tissue sections indicated an inverse correlation between the strength of CTGF expression and osteoblast maturation. Down-regulation of CTGF reporter expression also occurred during in vitro osteogenic differentiation. Collectively, our studies indicate that CTGF reporter mice selectively identify a subpopulation of bone marrow mesenchymal progenitor cells that reside in the trabecular bone region.

  6. Transcutaneous electrical acupoint stimulation alleviates the hyperandrogenism of polycystic ovarian syndrome rats by regulating the expression of P450arom and CTGF in the ovaries

    PubMed Central

    Qu, Fan; Liang, Yi; Zhou, Jue; Ma, Rui-Jie; Zhou, Jie; Wang, Fang-Fang; Wu, Yan; Fang, Jian-Qiao

    2015-01-01

    The present study was to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS) in alleviating the hyperandrogenism of polycystic ovarian syndrome (PCOS) model rats induced by testosterone propionate and the possible underlying mechanism. Thirty-six female Sprague-Dawley rats were randomly divided into normal control, PCOS model and TEAS groups with twelve rats in each group. The PCOS model rats were established by single injection of testosterone propionate at 9th day after birth, and the status of estrous cyclicity for each rat was observed. When the 8-week TEAS treatment completed, the weight of body, uterus and ovaries of the rats were respectively measured. The serum levels of total testosterone (TT), sex hormone binding globulin (SHBG), androstenedione, luteinizing hormone (LH), follicle stimulating hormone (FSH) and estradiol (E2) were detected. The mRNA and protein expression levels of aromatase cytochrome P450 (P450arom) and connective tissue growth factor (CTGF) in the ovaries of the rats were respectively measured with real-time quantitative PCR and immunohistochemistry. The TEAS treatment significantly improved the estrous cycles of the PCOS rats and the TEAS group displayed significantly lower average body and ovaries weights than the PCOS model group (P < 0.05). TEAS significantly decreased the serum TT, free androgen index (FAI), androstenedione and LH/FSH levels, and increased the serum FSH levels of the PCOS rats (P < 0.05). The TEAS treatment significantly increased the P450arom mRNA as well as protein expression levels and significantly decreased the CTGF mRNA as well as protein expression levels in the ovaries of the PCOS rats (P < 0.05). We concluded that it is through regulating the P450arom and CTGF expression levels in the ovaries that TEAS significantly alleviates the hyperandrogenism of PCOS rats induced by testosterone propionate. PMID:26221326

  7. Transcutaneous electrical acupoint stimulation alleviates the hyperandrogenism of polycystic ovarian syndrome rats by regulating the expression of P450arom and CTGF in the ovaries.

    PubMed

    Qu, Fan; Liang, Yi; Zhou, Jue; Ma, Rui-Jie; Zhou, Jie; Wang, Fang-Fang; Wu, Yan; Fang, Jian-Qiao

    2015-01-01

    The present study was to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS) in alleviating the hyperandrogenism of polycystic ovarian syndrome (PCOS) model rats induced by testosterone propionate and the possible underlying mechanism. Thirty-six female Sprague-Dawley rats were randomly divided into normal control, PCOS model and TEAS groups with twelve rats in each group. The PCOS model rats were established by single injection of testosterone propionate at 9th day after birth, and the status of estrous cyclicity for each rat was observed. When the 8-week TEAS treatment completed, the weight of body, uterus and ovaries of the rats were respectively measured. The serum levels of total testosterone (TT), sex hormone binding globulin (SHBG), androstenedione, luteinizing hormone (LH), follicle stimulating hormone (FSH) and estradiol (E2) were detected. The mRNA and protein expression levels of aromatase cytochrome P450 (P450arom) and connective tissue growth factor (CTGF) in the ovaries of the rats were respectively measured with real-time quantitative PCR and immunohistochemistry. The TEAS treatment significantly improved the estrous cycles of the PCOS rats and the TEAS group displayed significantly lower average body and ovaries weights than the PCOS model group (P < 0.05). TEAS significantly decreased the serum TT, free androgen index (FAI), androstenedione and LH/FSH levels, and increased the serum FSH levels of the PCOS rats (P < 0.05). The TEAS treatment significantly increased the P450arom mRNA as well as protein expression levels and significantly decreased the CTGF mRNA as well as protein expression levels in the ovaries of the PCOS rats (P < 0.05). We concluded that it is through regulating the P450arom and CTGF expression levels in the ovaries that TEAS significantly alleviates the hyperandrogenism of PCOS rats induced by testosterone propionate.

  8. Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro.

    PubMed

    Sonnylal, Sonali; Xu, Shiwen; Jones, Helen; Tam, Angela; Sreeram, Vivek R; Ponticos, Markella; Norman, Jill; Agrawal, Pankaj; Abraham, David; de Crombrugghe, Benoit

    2013-05-15

    Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia, and basal cells stained positive for αSMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of phosphorylated p38 and phosphorylated Erk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells co-expressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGFβ, CTGF-specific siRNA-mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of α-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis.

  9. Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro

    PubMed Central

    Sonnylal, Sonali; Xu, Shiwen; Jones, Helen; Tam, Angela; Sreeram, Vivek R.; Ponticos, Markella; Norman, Jill; Agrawal, Pankaj; Abraham, David; de Crombrugghe, Benoit

    2013-01-01

    Summary Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia, and basal cells stained positive for αSMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of phosphorylated p38 and phosphorylated Erk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells co-expressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGFβ, CTGF-specific siRNA-mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of α-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis. PMID:23525012

  10. The Skeletal Site-Specific Role of Connective Tissue Growth Factor in Prenatal Osteogenesis

    PubMed Central

    Lambi, Alex G.; Pankratz, Talia L.; Mundy, Christina; Gannon, Maureen; Barbe, Mary F.; Richtsmeier, Joan T.; Popoff, Steven N.

    2013-01-01

    Background Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted. Results We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-β-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype. Conclusions We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation. PMID:23073844

  11. Arecoline-stimulated connective tissue growth factor production in human buccal mucosal fibroblasts: Modulation by curcumin.

    PubMed

    Deng, Yi-Ting; Chen, Hsin-Ming; Cheng, Shih-Jung; Chiang, Chun-Pin; Kuo, Mark Yen-Ping

    2009-09-01

    Connective tissue growth factor (CTGF) is associated with the onset and progression of fibrosis in many human tissues. Areca nut (AN) chewing is the most important etiological factor in the pathogenesis of oral submucous fibrosis (OSF). We immunohistochemically examined the expression of CTGF protein in 20 cases of OSF and found positive CTGF staining in fibroblasts and endothelial cells in all cases. Western blot analysis showed that arecoline, a main alkaloid found in AN, stimulated CTGF synthesis in a dose- and time-dependent manner in buccal mucosal fibroblasts. Constitutive overexpression of CTGF during AN chewing may enhance the fibrotic activity in OSF and play a role in the pathogenesis of OSF. Pretreatment with NF-kappaB inhibitor Bay 11-7082, JNK inhibitor SP600125, p38 MAPK inhibitor SB203580 and antioxidant N-acetyl-l-cysteine, but not ERK inhibitor PD98059, significantly reduced arecoline-induced CTGF synthesis. Furthermore, curcumin completely inhibited arecoline-induced CTGF synthesis and the inhibition is dose-dependent. These results indicated that arecoline-induced CTGF synthesis was mediated by ROS, NF-kappaB, JNK, P38 MAPK pathways and curcumin could be a useful agent in controlling OSF.

  12. Up-regulation of connective tissue growth factor in endothelial cells by the microtubule-destabilizing agent combretastatin A-4.

    PubMed

    Samarin, Jana; Rehm, Margot; Krueger, Bettina; Waschke, Jens; Goppelt-Struebe, Margarete

    2009-02-01

    Incubation of microvascular endothelial cells with combretastatin A-4 phosphate (CA-4P), a microtubule-destabilizing compound that preferentially targets tumor vessels, altered cell morphology and induced scattering of Golgi stacks. Concomitantly, CA-4P up-regulated connective tissue growth factor (CTGF/CCN2), a pleiotropic factor with antiangiogenic properties. In contrast to the effects of other microtubule-targeting agents such as colchicine or nocodazole, up-regulation of CTGF was only detectable in sparse cells, which were not embedded in a cell monolayer. Furthermore, CA-4P induced CTGF expression in endothelial cells, forming tube-like structures on basement membrane gels. Up-regulation of CTGF by CA-4P was dependent on Rho kinase signaling and was increased when p42/44 mitogen-activated protein kinase was inhibited. Additionally, FoxO transcription factors were identified as potent regulators of CTGF expression in endothelial cells. Activation of FoxO transcription factors by inhibition of phosphatidylinositol 3-kinase/AKT signaling resulted in a synergistic increase in CA-4P-mediated CTGF induction. CA-4P-mediated expression of CTGF was thus potentiated by the inhibition of kinase pathways, which are targets of novel antineoplastic drugs. Up-regulation of CTGF by low concentrations of CA-4P may thus occur in newly formed tumor vessels and contribute to the microvessel destabilization and antiangiogenic effects of CA-4P observed in vivo.

  13. Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma

    PubMed Central

    Jorgensen, Marda; Song, Joanna; Zhou, Junmei; Liu, Chen

    2016-01-01

    Hepatic stem/progenitor cells (HPC) reside quiescently in normal biliary trees and are activated in the form of ductular reactions during severe liver damage when the replicative ability of hepatocytes is inhibited. HPC niches are full of profibrotic stimuli favoring scarring and hepatocarcinogenesis. The Cyr61/CTGF/NOV (CCN) protein family consists of six members, CCN1/CYR61, CCN2/CTGF, CCN3/NOV, CCN4/WISP1, CCN5/WISP2, and CCN6/WISP3, which function as extracellular signaling modulators to mediate cell-matrix interaction during angiogenesis, wound healing, fibrosis, and tumorigenesis. This study investigated expression patterns of CCN proteins in HPC and cholangiocarcinoma (CCA). Mouse HPC were induced by the biliary toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Differential expression patterns of CCN proteins were found in HPC from DDC damaged mice and in human CCA tumors. In addition, we utilized reporter mice that carried Ccn2/Ctgf promoter driven GFP and detected strong Ccn2/Ctgf expression in epithelial cell adhesion molecule (EpCAM)+ HPC under normal conditions and in DDC-induced liver damage. Abundant CCN2/CTGF protein was also found in cytokeratin 19 (CK19)+ human HPC that were surrounded by α-smooth muscle actin (α-SMA)+ myofibroblast cells in intrahepatic CCA tumors. These results suggest that CCN proteins, particularly CCN2/CTGF, function in HPC activation and CCA development. PMID:27829832

  14. Yap/Taz transcriptional activity is essential for vascular regression via Ctgf expression and actin polymerization

    PubMed Central

    Nagasawa-Masuda, Ayumi; Terai, Kenta

    2017-01-01

    Vascular regression is essential to remove redundant vessels during the formation of an efficient vascular network that can transport oxygen and nutrient to every corner of the body. However, no mechanism is known to explain how major blood vessels regress during development. Here we use the dorsal part of the caudal vein plexus (dCVP) in Zebrafish to investigate the mechanism of regression and discover a new role of Yap/Taz in vascular regression. During regression, Yap/Taz is activated by blood circulation in the endothelial cells. This leads to induction of Ctgf and actin polymerization. Interference with Yap/Taz activation decreased Ctgf production, which decreased actin polymerization and vascular regression. These results implicate a novel role of Yap/Taz in vascular regression. PMID:28369143

  15. Activin A-Smad Signaling Mediates Connective Tissue Growth Factor Synthesis in Liver Progenitor Cells

    PubMed Central

    Ding, Ze-Yang; Jin, Guan-Nan; Wang, Wei; Sun, Yi-Min; Chen, Wei-Xun; Chen, Lin; Liang, Hui-Fang; Datta, Pran K.; Zhang, Ming-Zhi; Zhang, Bixiang; Chen, Xiao-Ping

    2016-01-01

    Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in LPCs remains elusive. In this study, we report that Activin A is an inducer of CTGF/CCN2 in LPCs. Here we show that expression of both Activin A and CTGF/CCN2 were upregulated in the cirrhotic liver, and the expression of Activin A positively correlates with that of CTGF/CCN2 in liver tissues. We go on to show that Activin A induced de novo synthesis of CTGF/CCN2 in LPC cell lines LE/6 and WB-F344. Furthermore, Activin A contributed to autonomous production of CTGF/CCN2 in liver progenitor cells (LPCs) via activation of the Smad signaling pathway. Smad2, 3 and 4 were all required for this induction. Collectively, these results provide evidence for the fibrotic role of LPCs in the liver and suggest that the Activin A-Smad-CTGF/CCN2 signaling in LPCs may be a therapeutic target of liver fibrosis. PMID:27011166

  16. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

    PubMed Central

    Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

    2015-01-01

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

  17. Connective Tissue Growth Factor Is Required for Normal Follicle Development and Ovulation

    PubMed Central

    Nagashima, Takashi; Kim, Jaeyeon; Li, Qinglei; Lydon, John P.; DeMayo, Francesco J.; Lyons, Karen M.

    2011-01-01

    Connective tissue growth factor (CTGF) is a cysteine-rich protein the synthesis and secretion of which are hypothesized to be selectively regulated by activins and other members of the TGF-β superfamily. To investigate the in vivo roles of CTGF in female reproduction, we generated Ctgf ovarian and uterine conditional knockout (cKO) mice. Ctgf cKO mice exhibit severe subfertility and multiple reproductive defects including disrupted follicle development, decreased ovulation rates, increased numbers of corpus luteum, and smaller but functionally normal uterine horns. Steroidogenesis is disrupted in the Ctgf cKO mice, leading to increased levels of serum progesterone. We show that disrupted follicle development is accompanied by a significant increase in granulosa cell apoptosis. Moreover, despite normal cumulus expansion, Ctgf cKO mice exhibit a significant decrease in oocytes ovulated, likely due to impaired ovulatory process. During analyses of mRNA expression, we discovered that Ctgf cKO granulosa cells show gene expression changes similar to our previously reported granulosa cell-specific knockouts of activin and Smad4, the common TGF-β family intracellular signaling protein. We also discovered a significant down-regulation of Adamts1, a progesterone-regulated gene that is critical for the remodeling of extracellular matrix surrounding granulosa cells of preovulatory follicles. These findings demonstrate that CTGF is a downstream mediator in TGF-β and progesterone signaling cascades and is necessary for normal follicle development and ovulation. PMID:21868453

  18. Connective tissue growth factor is required for normal follicle development and ovulation.

    PubMed

    Nagashima, Takashi; Kim, Jaeyeon; Li, Qinglei; Lydon, John P; DeMayo, Francesco J; Lyons, Karen M; Matzuk, Martin M

    2011-10-01

    Connective tissue growth factor (CTGF) is a cysteine-rich protein the synthesis and secretion of which are hypothesized to be selectively regulated by activins and other members of the TGF-β superfamily. To investigate the in vivo roles of CTGF in female reproduction, we generated Ctgf ovarian and uterine conditional knockout (cKO) mice. Ctgf cKO mice exhibit severe subfertility and multiple reproductive defects including disrupted follicle development, decreased ovulation rates, increased numbers of corpus luteum, and smaller but functionally normal uterine horns. Steroidogenesis is disrupted in the Ctgf cKO mice, leading to increased levels of serum progesterone. We show that disrupted follicle development is accompanied by a significant increase in granulosa cell apoptosis. Moreover, despite normal cumulus expansion, Ctgf cKO mice exhibit a significant decrease in oocytes ovulated, likely due to impaired ovulatory process. During analyses of mRNA expression, we discovered that Ctgf cKO granulosa cells show gene expression changes similar to our previously reported granulosa cell-specific knockouts of activin and Smad4, the common TGF-β family intracellular signaling protein. We also discovered a significant down-regulation of Adamts1, a progesterone-regulated gene that is critical for the remodeling of extracellular matrix surrounding granulosa cells of preovulatory follicles. These findings demonstrate that CTGF is a downstream mediator in TGF-β and progesterone signaling cascades and is necessary for normal follicle development and ovulation.

  19. Conditional overexpression of connective tissue growth factor disrupts postnatal lung development.

    PubMed

    Wu, Shu; Platteau, Astrid; Chen, Shaoyi; McNamara, George; Whitsett, Jeffrey; Bancalari, Eduardo

    2010-05-01

    Connective tissue growth factor (CTGF) is a member of an emerging family of immediate-early gene products that coordinates complex biological processes during development, differentiation, and tissue repair. Overexpression of CTGF is associated with mechanical ventilation with high tidal volume and oxygen exposure in newborn lungs. However, the role of CTGF in postnatal lung development and remodeling is not well understood. In the present study, a double-transgenic mouse model was generated with doxycycline-inducible overexpression of CTGF in respiratory epithelial cells. Overexpression of CTGF from Postnatal Days 1-14 resulted in thicker alveolar septa and decreased secondary septal formation. This is correlated with increased myofibroblast differentiation and disorganized elastic fiber deposition in alveolar septa. Overexpression of CTGF also decreased alveolar capillary network formation. There were increased alpha-smooth muscle actin expression and collagen deposition, and dramatic thickening in the peribronchial/peribronchiolar and perivascular regions in the double-transgenic lungs. Furthermore, overexpression of CTGF increased integrin-linked kinase expression, activated its downstream signaling target, Akt, as well as increased mRNA expression of fibronectin. These data demonstrate that overexpression of CTGF disrupts alveologenesis and capillary formation, and induces fibrosis during the critical period of alveolar development. These histologic changes are similar to those observed in lungs of infants with bronchopulmonary dysplasia.

  20. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    PubMed

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  1. Activin A-Smad Signaling Mediates Connective Tissue Growth Factor Synthesis in Liver Progenitor Cells.

    PubMed

    Ding, Ze-Yang; Jin, Guan-Nan; Wang, Wei; Sun, Yi-Min; Chen, Wei-Xun; Chen, Lin; Liang, Hui-Fang; Datta, Pran K; Zhang, Ming-Zhi; Zhang, Bixiang; Chen, Xiao-Ping

    2016-03-22

    Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in LPCs remains elusive. In this study, we report that Activin A is an inducer of CTGF/CCN2 in LPCs. Here we show that expression of both Activin A and CTGF/CCN2 were upregulated in the cirrhotic liver, and the expression of Activin A positively correlates with that of CTGF/CCN2 in liver tissues. We go on to show that Activin A induced de novo synthesis of CTGF/CCN2 in LPC cell lines LE/6 and WB-F344. Furthermore, Activin A contributed to autonomous production of CTGF/CCN2 in liver progenitor cells (LPCs) via activation of the Smad signaling pathway. Smad2, 3 and 4 were all required for this induction. Collectively, these results provide evidence for the fibrotic role of LPCs in the liver and suggest that the Activin A-Smad-CTGF/CCN2 signaling in LPCs may be a therapeutic target of liver fibrosis.

  2. Connective Tissue Growth Factor Is Involved in Structural Retinal Vascular Changes in Long-Term Experimental Diabetes

    PubMed Central

    Van Geest, Rob J.; Leeuwis, Jan Willem; Dendooven, Amélie; Pfister, Frederick; Bosch, Klazien; Hoeben, Kees A.; Vogels, Ilse M.C.; Van der Giezen, Dionne M.; Dietrich, Nadine; Hammes, Hans-Peter; Goldschmeding, Roel; Klaassen, Ingeborg; Van Noorden, Cornelis J.F.

    2014-01-01

    Early retinal vascular changes in the development of diabetic retinopathy (DR) include capillary basal lamina (BL) thickening, pericyte loss and the development of acellular capillaries. Expression of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family member CCN2 or connective tissue growth factor (CTGF), a potent inducer of the expression of BL components, is upregulated early in diabetes. Diabetic mice lacking one functional CTGF allele (CTGF+/−) do not show this BL thickening. As early events in DR may be interrelated, we hypothesized that CTGF plays a role in the pathological changes of retinal capillaries other than BL thickening. We studied the effects of long-term (6-8 months) streptozotocin-induced diabetes on retinal capillary BL thickness, numbers of pericytes and the development of acellular capillaries in wild type and CTGF+/− mice. Our results show that an absence of BL thickening of retinal capillaries in long-term diabetic CTGF+/− mice is associated with reduced pericyte dropout and reduced formation of acellular capillaries. We conclude that CTGF is involved in structural retinal vascular changes in diabetic rodents. Inhibition of CTGF in the eye may therefore be protective against the development of DR. PMID:24217924

  3. A virus-like particle-based connective tissue growth factor vaccine suppresses carbon tetrachloride-induced hepatic fibrosis in mice

    PubMed Central

    Li, Shuang; Lv, Yi-Fei; Su, Hou-Qiang; Zhang, Qian-Nan; Wang, Li-Rong; Hao, Zhi-Ming

    2016-01-01

    Connective tissue growth factor (CTGF) has been recognized as a central mediator and promising therapeutic target in hepatic fibrosis. In this study, we generated a novel virus-like particle (VLP) CTGF vaccine by inserting the 138–159 amino acid (aa) fragment of CTGF into the central c/e1 epitope of C-terminus truncated hepatitis B virus core antigen (HBc, aa 1–149) using a prokaryotic expression system. Immunization of BALB/c mice with the VLP vaccine efficiently elicited the production of anti-CTGF neutralizing antibodies. Vaccination with this CTGF vaccine significantly protected BALB/c mice from carbon tetrachloride (CCl4)-induced hepatic fibrosis, as indicated by decreased hepatic hydroxyproline content and lower fibrotic score. CCl4 intoxication-induced hepatic stellate cell activation was inhibited by the vaccination, as indicated by decreased α-smooth muscle actin expression and Smad2 phosphorylation. Vaccination against CTGF also attenuated the over-expression of some profibrogenic factors, such as CTGF, transforming growth factor-β1, platelet-derived growth factor-B and tissue inhibitor of metalloproteinase-1 in the fibrotic mouse livers, decreased hepatocyte apoptosis and accelerated hepatocyte proliferation in the fibrotic mouse livers. Our results clearly indicate that vaccination against CTGF inhibits fibrogenesis, alleviates hepatocyte apoptosis and facilitate hepatic regeneration. We suggest that the vaccine should be developed into an effective therapeutic measure for hepatic fibrosis. PMID:27562139

  4. Connective Tissue Growth Factor Promotes Pulmonary Epithelial Cell Senescence and Is Associated with COPD Severity.

    PubMed

    Jang, Jun-Ho; Chand, Hitendra S; Bruse, Shannon; Doyle-Eisele, Melanie; Royer, Christopher; McDonald, Jacob; Qualls, Clifford; Klingelhutz, Aloysius J; Lin, Yong; Mallampalli, Rama; Tesfaigzi, Yohannes; Nyunoya, Toru

    2017-04-01

    The purpose of this study was to determine whether expression of connective tissue growth factor (CTGF) protein in chronic obstructive pulmonary disease (COPD) is consistent in humans and animal models of COPD and to investigate the role of this protein in lung epithelial cells. CTGF in lung epithelial cells of ex-smokers with COPD was compared with ex-smokers without COPD by immunofluorescence. A total of twenty C57Bl/6 mice and sixteen non-human primates (NHPs) were exposed to cigarette smoke (CS) for 4 weeks. Ten mice of these CS-exposed mice and eight of the CS-exposed NHPs were infected with H3N2 influenza A virus (IAV), while the remaining ten mice and eight NHPs were mock-infected with vehicle as control. Both mRNA and protein expression of CTGF in lung epithelial cells of mice and NHPs were determined. The effects of CTGF overexpression on cell proliferation, p16 protein, and senescence-associated β-galactosidase (SA-β-gal) activity were examined in cultured human bronchial epithelial cells (HBECs). In humans, CTGF expression increased with increasing COPD severity. We found that protein expression of CTGF was upregulated in lung epithelial cells in both mice and NHPs exposed to CS and infected with IAV compared to those exposed to CS only. When overexpressed in HBECs, CTGF accelerated cellular senescence accompanied by p16 accumulation. Both CTGF and p16 protein expression in lung epithelia are positively associated with the severity of COPD in ex-smokers. These findings show that CTGF is consistently expressed in epithelial cells of COPD lungs. By accelerating lung epithelial senescence, CTGF may block regeneration relative to epithelial cell loss and lead to emphysema.

  5. "La Clave Profesional": Validation of a Vocational Guidance Instrument

    ERIC Educational Resources Information Center

    Mudarra, Maria J.; Lázaro Martínez, Ángel

    2014-01-01

    Introduction: The current study demonstrates empirical and cultural validity of "La Clave Profesional" (Spanish adaptation of Career Key, Jones's test based Holland's RIASEC model). The process of providing validity evidence also includes a reflection on personal and career development and examines the relationahsips between RIASEC…

  6. Exposure-dependent increases in IL-1beta, substance P, CTGF, and tendinosis in flexor digitorum tendons with upper extremity repetitive strain injury.

    PubMed

    Fedorczyk, Jane M; Barr, Ann E; Rani, Shobha; Gao, Helen G; Amin, Mamta; Amin, Shreya; Litvin, Judith; Barbe, Mary F

    2010-03-01

    Upper extremity tendinopathies are associated with performance of forceful repetitive tasks. We used our rat model of repetitive strain injury to study changes induced in forelimb flexor digitorum tendons. Rats were trained to perform a high repetition high force (HRHF) handle-pulling task (12 reaches/min at 60 +/- 5% maximum pulling force [MPF]), or a low repetition negligible force (LRNF) reaching and food retrieval task (three reaches/min at 5 +/- 5% MPF), for 2 h/day in 30 min sessions, 3 days/week for 3-12 weeks. Forelimb grip strength was tested. Flexor digitorum tendons were examined at midtendon at the level of the carpal tunnel for interleukin (IL)-1beta, neutrophil, and macrophage influx, Substance P, connective tissue growth factor (CTGF), and periostin-like factor (PLF) immunoexpression, and histopathological changes. In HRHF rats, grip strength progressively decreased, while IL-1beta levels progressively increased in the flexor digitorum peritendon (para- and epitendon combined) and endotendon with task performance. Macrophage invasion was evident in week 6 and 12 HRHF peritendon but not endotendon. Also in HRHF rats, Substance P immunoexpression increased in week 12 peritendon as did CTGF- and PLF-immunopositive fibroblasts, the increased fibroblasts contributing greatly to peritendon thickening. Endotendon collagen disorganization was evident in week 12 HRHF tendons. LRNF tendons did not differ from controls, even at 12 weeks. Thus, we observed exposure-dependent changes in flexor digitorum tendons within the carpal tunnel, including increased inflammation, nociceptor-related neuropeptide immunoexpression, and fibrotic histopathology, changes associated with grip strength decline.

  7. Optimum scratch assay condition to evaluate connective tissue growth factor expression for anti-scar therapy.

    PubMed

    Moon, Heekyung; Yong, Hyeyoung; Lee, Ae-Ri Cho

    2012-02-01

    To evaluate a potential anti-scar therapy, we first need to have a reliable in vitro wound model to understand dermal fibroblast response upon cell injury and how cytokine levels are changed upon different wound heal phases. An in vitro wound model with different scratch assay conditions on primary human foreskin fibroblast monolayer cultures was prepared and cytokine levels and growth properties were evaluated with the aim of determining optimum injury conditions and observation time. Morphological characteristics of differently scratched fibroblasts from 0 to 36 h post injury (1 line, 2 lines and 3 lines) were investigated. The expression of connective tissue growth factor, CTGF, which is a key mediator in hyper-tropic scarring, and relative intensity of CTGF as a function of time were determined by western blot and gelatin Zymography. After injury (1 line), CTGF level was increased more than 2-fold within 1 h and continuously increased up to 3-fold at 6 h and was leveled down to reach normal value at 36 h, at which cell migration was complete. In more serious injury (2 lines), higher expression of CTGF was observed. The down regulation of CTGF expression after CTGF siRNA/lipofectamine transfection in control, 1 line and 2 lines scratch conditions were 40%, 75% and 55%, respectively. As a model anti-CTGF based therapy, CTGF siRNA with different ratios of linear polyethyleneimine (PEI) complexes (1:1, 1:5, 1:10, 1:20 and 1:30) were prepared and down-regulation efficacy of CTGF was evaluated with our optimized scratch assay, which is 1 line injury at 6 h post injury observation time. As the cationic linear PEI ratio increased, the down regulation efficacy was increased from 20% (1:20) to 55% (1:30). As CTGF level was increased to the highest at 6 h and leveled down afterwards, CTGF level at 6 h could provide the most sensitive response upon CTGF siRNA transfection. The scratch assay in the present study can be employed as a useful experimental tool to differentiate

  8. Molecular control of vascular development by the matricellular proteins CCN1 (Cyr61) and CCN2 (CTGF).

    PubMed

    Chaqour, Brahim

    2013-01-01

    The circulatory system is the first hierarchically ordered network to form during the development of vertebrates as it is an indispensable means of adequate oxygen and nutrient delivery to developing organs. During the initial phase of vascular development, endothelial lineage-committed cells differentiate, migrate, and coalesce to form the central large axial vessels and their branches. The subsequent phase of vessel expansion (i.e., angiogenesis) involves a cascade of events including endothelial cell migration, proliferation, formation of an immature capillary structure, recruitment of mural cells and deposition of a basement membrane to yield a functional vasculature. These series of events are tightly regulated by the coordinated expression of several angiogenic, morphogenic and guidance factors. The extracellular matrix (ECM) is synthesized and secreted by embryonic cells at the earliest stages of development and forms a pericellular network of bioactive stimulatory and inhibitory angiogenesis regulatory factors. Here we describe the role of a subset of inducible immediate-early gene-encoded, ECM-associated integrin- and heparin-binding proteins referred to as CCN1 (or Cyr61) and CCN2 (or CTGF) and their function in the development of the vascular system. Gene-targeting experiments in mice have identified CCN1 and CCN2 as critical rate-limiting determinants of endothelial cell differentiation and quiescence, mural cell recruitment and basement membrane formation during embryonic vascular development. Emphasis will be placed on the regulation and function of these molecules and their contextual mode of action during vascular development. Further understanding of the mechanisms of CCN1- and CCN2-mediated blood vessel expansion and remodeling would enhance the prospects that these molecules provide for the development of new treatments for vascular diseases.

  9. Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor.

    PubMed

    Yang, Jibing; Velikoff, Miranda; Canalis, Ernesto; Horowitz, Jeffrey C; Kim, Kevin K

    2014-04-15

    Fibrogenesis involves a pathological accumulation of activated fibroblasts and extensive matrix remodeling. Profibrotic cytokines, such as TGF-β, stimulate fibroblasts to overexpress fibrotic matrix proteins and induce further expression of profibrotic cytokines, resulting in progressive fibrosis. Connective tissue growth factor (CTGF) is a profibrotic cytokine that is indicative of fibroblast activation. Epithelial cells are abundant in the normal lung, but their contribution to fibrogenesis remains poorly defined. Profibrotic cytokines may activate epithelial cells with protein expression and functions that overlap with the functions of active fibroblasts. We found that alveolar epithelial cells undergoing TGF-β-mediated mesenchymal transition in vitro were also capable of activating lung fibroblasts through production of CTGF. Alveolar epithelial cell expression of CTGF was dramatically reduced by inhibition of Rho signaling. CTGF reporter mice demonstrated increased CTGF promoter activity by lung epithelial cells acutely after bleomycin in vivo. Furthermore, mice with lung epithelial cell-specific deletion of CTGF had an attenuated fibrotic response to bleomycin. These studies provide direct evidence that epithelial cell activation initiates a cycle of fibrogenic effector cell activation during progressive fibrosis. Therapy targeted at epithelial cell production of CTGF offers a novel pathway for abrogating this progressive cycle and limiting tissue fibrosis.

  10. High expression of connective tissue growth factor accelerates dissemination of leukaemia.

    PubMed

    Wells, J E; Howlett, M; Halse, H M; Heng, J; Ford, J; Cheung, L C; Samuels, A L; Crook, M; Charles, A K; Cole, C H; Kees, U R

    2016-09-01

    To improve treatment of acute lymphoblastic leukaemia (ALL), a better understanding of disease development is needed to tailor new therapies. Connective tissue growth factor (CTGF/CCN2) is highly expressed in leukaemia cells from the majority of paediatric patients with B-lineage ALL (pre-B ALL). CTGF is a matricellular protein and plays a role in aggressive cancers. Here we have genetically engineered leukaemia cells to modulate CTGF expression levels. Elevated CTGF levels accelerated disease dissemination and reduced survival in NOD/SCID mice. In vitro studies showed that CTGF protein induces stromal cell proliferation, promotes adhesion of leukaemia cells to stromal cells and leads to overexpression of genes associated with cell cycle and synthesis of extracellular matrix (ECM). Corresponding data from our leukaemia xenograft models demonstrated that CTGF leads to increased proliferation of non-leukaemia cells and deposition of ECM in the bone marrow. We document for the first time a functional role of CTGF in altering disease progression in a lymphoid malignancy. The findings provide support for targeting the bone marrow microenvironment in aggressive forms of leukaemia.

  11. Increased connective tissue growth factor associated with cardiac fibrosis in the mdx mouse model of dystrophic cardiomyopathy.

    PubMed

    Au, Carol G; Butler, Tanya L; Sherwood, Megan C; Egan, Jonathan R; North, Kathryn N; Winlaw, David S

    2011-02-01

    Cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disorder. A major feature of the hearts of DMD patients and the mdx mouse model of the disease is cardiac fibrosis. Connective tissue growth factor (CTGF) is involved in the fibrotic process in many organs. This study utilized the mdx mouse model to assess the role of CTGF and other extracellular matrix components during the development of fibrosis in the dystrophic heart. Left ventricular function of mdx and control mice at 6, 29 and 43 weeks was measured by echocardiography. Young (6 weeks old) mdx hearts had normal function and histology. At 29 weeks of age, mdx mice developed cardiac fibrosis and increased collagen expression. The onset of fibrosis was associated with increased CTGF transcript and protein expression. Increased intensity of CTGF immunostaining was localized to fibrotic areas in mdx hearts. The upregulation of CTGF was also concurrent with increased expression of tissue inhibitor of matrix metalloproteinases (TIMP-1). These changes persisted in 43 week old mdx hearts and were combined with impaired cardiac function and increased gene expression of transforming growth factor (TGF)-β1 and matrix metalloproteinases (MMP-2, MMP-9). In summary, an association was observed between cardiac fibrosis and increased CTGF expression in the mdx mouse heart. CTGF may be a key mediator of early and persistent fibrosis in dystrophic cardiomyopathy.

  12. Inhibition of connective tissue growth factor attenuates paraquat-induced lung fibrosis in a human MRC-5 cell line.

    PubMed

    Huang, Min; Yang, Huifang; Zhu, Lingqin; Li, Honghui; Zhou, Jian; Zhou, Zhijun

    2016-11-01

    Chronic exposure to Paraquat (PQ) may result in progressive pulmonary fibrosis and subsequent chronic obstructive pulmonary malfunction. Connective tissue growth factor (CTGF) has been proposed as a key determinant in the development of lung fibrosis. We investigated thus whether knock down of CTGF can prevent human lung fibroblasts (MRC-5) activation and proliferation with the subsequent inhibition of PQ-induced fibrosis. MRC-5 was transfected with CTGF-siRNAs and exposed to different concentrations of PQ. The siRNA-silencing efficacy was evaluated using western blotting analyses, qRT-PCR and flow cytometry. Next, the viability and migration of MRC-5 was determined. MMP-2, MMP-9, and TIMP-1 accumulation were quantified to evaluate the lung fibrosis exposure to PQ. Over expression of CTGF mRNA was observed in human MRC-5 cell as early as 6 h following PQ stimulation. CTGF gene expression in MRC-5 cells was substantially reduced by RNAi, which significantly suppressed the expression of the lung fibrosis markers such as tissue inhibitor of metalloproteinase-2 (TIMP-2), Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9) that were stimulated by PQ. Inhibition of CTGF expression suppressed impeded the proliferation and migration ability of MRC-5 cells and resulted in cell-extracellular matrix (ECM) protein accumulation in cells. Our results suggest that CTGF promoted the development of PQ-induced lung fibrosis in collaboration with transforming growth factor β1 (TGFβ1). Furthermore, the observed arresting effects of CTGF knock down during this process suggested that CTGF is the potential target site for preventing PQ-induced pulmonary fibrosis. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1620-1626, 2016.

  13. Connective Tissue Growth Factor Regulates Cardiac Function and Tissue Remodeling in a Mouse Model of Dilated Cardiomyopathy

    PubMed Central

    Koshman, Yevgeniya E.; Sternlicht, Mark D.; Kim, Taehoon; O'Hara, Christopher P.; Koczor, Christopher A.; Lewis, William; Seeley, Todd W.; Lipson, Kenneth E.; Samarel, Allen M.

    2015-01-01

    Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective Tissue Growth Factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic function in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling were elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted. PMID:26549358

  14. Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis.

    PubMed

    Gerritsen, K G F; Bovenschen, N; Nguyen, T Q; Sprengers, D; Koeners, M P; van Koppen, A N; Joles, J A; Goldschmeding, R; Kok, R J

    2016-12-01

    CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, full length CCN-2 is primarily eliminated by the liver via a fast RAP-sensitive, probably LRP1-dependent

  15. Connective tissue growth factor increases matrix metalloproteinase-2 and suppresses tissue inhibitor of matrix metalloproteinase-2 production by cultured renal interstitial fibroblasts.

    PubMed

    Yang, Min; Huang, Haichang; Li, Jingzi; Huang, Wen; Wang, Haiyan

    2007-01-01

    The involvement of gelatinase (matrix metalloproteinase-2 [MMP-2] and MMP-9) in the matrix remodeling and development of tubulointerstitial fibrosis has been studied recently, but relatively little is known about the regulators and the mechanisms controlling the activation and expression of gelatinase in renal fibroblasts. In these studies, the production and underlying signaling pathway for gelatinase by exogenous connective tissue growth factor (CTGF) treatment were investigated. Here, we show that CTGF acts as a potent promoter of the activation and expression of MMP-2, but not MMP-9 in normal rat kidney fibroblasts cell line (NRK-49F). We found that CTGF significantly increased the activity of MMP-2, as well as MMP-2 protein in conditioned medium and MMP-2 mRNA levels in cells. In studies to address the mechanisms involved in the regulation of MMP-2 activity, we found that the tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), the inhibitor of MMP-2, decreased significantly when cells were treated with CTGF. Further studies showed that extracellular signal-regulated kinase (ERK) signaling is responsible for most of the CTGF-induced MMP-2 expression and TIMP-2 suppression. When NRK-49F fibroblasts were incubated with CTGF, activation of ERK1/2 signaling was observed. Suppression of ERK1/2 activation with nontoxic concentrations of PD98059, a specific inhibitor of ERK activation, was associated with a reduction of CTGF-stimulated MMP-2 activity and protein expression. In addition, the CTGF-mediated reduction of TIMP-2 activity and protein expression was prevented when ERK1/2 activation was inhibited by PD98059. These results provide evidence that CTGF augments activation of MMP-2 through an effect on MMP-2 protein expression and TIMP-2 suppression, and that these effects are dependent on the activation of the ERK1/2 pathway.

  16. The specificity of expertise: for whom is the clave pattern the "key" to salsa music?

    PubMed

    Getz, L M; Barton, S; Kubovy, M

    2014-10-01

    Each Latin salsa music style is associated with a characteristic clave pattern that constitutes an essential structure for performers. In this article we asked what types of expertise are needed to detect the correct salsa-clave pairing. Using two clave patterns (the 3-2 and 2-3 son clave) and three manipulated alternatives, we asked listeners to choose the correct clave pattern for a variety of bomba, calypso, mambo and merengue excerpts. The results of Studies 1 and 2 show that listeners unfamiliar with salsa were unable to detect the correct salsa-clave pairing. Listeners who had some music training or were familiar with salsa detected the need for syncopation but not the specific pairing. Only musicians well-acquainted with salsa correctly detected the salsa-clave pairing. Studies 3 and 4 showed that incorrect choices were not due to an inability to distinguish between the alternatives: both adults and five-year-olds could easily tell apart the various patterns we used. We conclude that the distinction between the 2-3 and 3-2 claves is not inherent in the music itself, but rather is a convention to be learned through exposure and training. We discuss the results using an analogy to language learning.

  17. Expression of transcription factors Slug in the lens epithelial cells undergoing epithelial-mesenchymal transition induced by connective tissue growth factor

    PubMed Central

    Wang, Ying-Na; Qin, Li; Li, Jing-Ming; Chen, Li; Pei, Cheng

    2015-01-01

    AIM To investigate the expression of transcription factors Slug in human lens epithelial cells (HLECs) undergoing epithelial-mesenchymal transition (EMT) induced by connective tissue growth factor (CTGF). METHODS HLECs were treated with CTGF of different concentrations (20, 50 and 100 ng/mL) or without CTGF (control) for 24h. The morphological changes of HLECs were analysed by microscopy. The expression and cellular localization of Slug was evaluated by immumo-fluorescence. Expressions of Slug, E-cadherin and alpha smooth muscle actin (α-SMA) were further determined by Western blot analysis. RESULTS HLECs showed spidle fibrolasts-like characteristics and loosely connected each other after CTGF treatment. The immuno-fluorescence staining indicated that Slug was localized in the nuclei and its expression was induced by CTGF. The relative expressions of Slug protein were 1.64±0.11, 1.96 ±0.03, 3.12 ±0.10, and 4.08±0.14, respectively, in response to control group and treatment with CTGF of 20, 50 and 100 ng/mL (F=443.86, P<0.01). The increased Slug protein levels were correlated well with up-expression of α-SMA (0.78±0.05, 0.85±0.06, 2.17±0.15, 2.86±0.10; F=449.85, P<0.01) and down-expression of E-cadherin (2.50±0.11, 1.79±0.26, 1.05±0.14, 0.63±0.08; F=101.55, P<0.01). CONCLUSION Transcription factor Slug may be involved in EMT of HLECs induced by CTGF in vitro. PMID:26558194

  18. Comparison of TGF-β, PDGF, and CTGF in hepatic fibrosis models using DMN, CCl4, and TAA.

    PubMed

    Park, Hye-Jung; Kim, Hyeong-Geug; Wang, Jing-Hua; Choi, Min-Kyung; Han, Jong-Min; Lee, Jin-Seok; Son, Chang-Gue

    2016-01-01

    Three chemotoxins including dimethylnitrosamine (DMN), carbon tetrachloride (CCl4), and thioacetamide (TAA) are commonly used in hepatofibrotic models. We aimed to draw characteristics of histopathology and pro-fibrogenic cytokines including TGF-β, PDGF and CTGF among three models. Rats were divided into six groups and intra-peritoneally injected with DMN (10 mg/kg, for three weeks, three consecutive days weekly), CCl4 (1.6 g/kg, for 10 weeks, twice weekly), TAA (200 mg/kg, for 12 weeks, twice weekly) or their corresponded treatment for each control group. The liver weights were decreased in DMN model, but not other models. Ascites were occurred as 3-, 2-, and 7-rats in DMN, CCl4, and TAA model, respectively. The lipid peroxidation was highest in CCl4 model, serum levels of liver enzymes were increased as similar severity. The hepatofibrotic alterations were remarkable in DMN and TAA model, but not CCl4 as evidenced by the Masson trichrome staining and hydroxyproline. The immunohistochemistry for α-SAM showed that the DMN model was most severely enhanced than other models. On the other hand, hepatic tissue levels of pro-fibrogenic cytokines including TGF-β, PDGF, and CTGF were generally increased in three models, but totally different among models or measurement resources. Especially, serum levels of three cytokines were remarkably increased by CCl4 injection and CTGF levels in both hepatic tissue and serum were highest in CCl4 group. Our results firstly demonstrated comparative study for features of morphological finding and pro-fibrogenic cytokines in serum and hepatic protein levels among three models. Above results would be a helpful reference for hepatofibrotic studies.

  19. Role of connective tissue growth factor in vascular and renal damage associated with hypertension in rats. Interactions with angiotensin II.

    PubMed

    de las Heras, Natalia; Ruiz-Ortega, Marta; Rupérez, Mónica; Sanz-Rosa, David; Miana, María; Aragoncillo, Paloma; Mezzano, Sergio; Lahera, Vicente; Egido, Jesus; Cachofeiro, Victoria

    2006-12-01

    We have evaluated the role of connective tissue growth factor (CTGF) in vascular and renal damage associated with hypertension and possible interactions with angiotensin II (Ang II). Spontaneously hypertensive rats (SHR) were treated with either the Ang II receptor antagonist candesartan (C;2 mg/Kg(-1)/day(-1)) or antihypertensive triple therapy (TT; in mg/Kg(-1)/day(-1);20 hydralazine +7 hydrochlorothiazide +0.15 reserpine) for 10 weeks. Wistar Kyoto rats were used as a normotensive control group. Hypertension was associated with an increase in aortic media area, media-to-lumen ratio and collagen density. Kidneys from SHR showed minimum renal alterations. Aorta and renal gene expression and immunostaining of CTGF were higher in SHR. Candesartan decreased arterial pressure, aortic media area, media-to-lumen ratio and collagen density. However, although arterial pressure decrease was comparable for both treatments, TT partially reduced these parameters. Candesartan-treated rats showed lower levels of vascular CTGF expression, aortic media area, media-to-lumen ratio and collagen density than TT-treated animals. Treatments improve renal damage and reduce renal gene expression and CTGF immunostaining in SHR in a similar manner. The results show that vascular and renal damage is associated with stimulation of CTGF gene and protein content. These results also might suggest that CTGF could be one downstream mediator of Ang II in hypertension-associated organ damage in SHR.

  20. Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-β1-connective tissue growth factor signalling cascade.

    PubMed

    Huang, Jiqian; Matavelli, Luis C; Siragy, Helmy M

    2011-04-01

    1. Transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) are expressed in renal glomeruli, and contribute to the development of diabetic nephropathy. Recently, we showed that (pro)renin receptor (PRR) is upregulated in the kidneys of the streptozocin (STZ)-induced diabetes rat model. We hypothesized that in the presence of hyperglycaemia, increased renal PRR expression contributes to enhanced TGF-β1-CTGF signalling activity, leading to the development of diabetic kidney disease. 2. In vivo and in vitro studies were carried out in Sprague-Dawley rats and rat mesangial cells (RMC). PRR blockade was achieved in vivo by treating STZ induced diabetes rats with the handle region peptide (HRP) of prorenin and in vitro by HRP or PRR siRNA in RMC. Angiotensin AT1 receptor blockade was achieved by valsartan treatment. 3. Results showed that expression of PRR, TGF-β1 and CTGF were upregulated in diabetic kidneys and RMC exposed to high glucose. Glucose exposure also induced PRR phosphorylation, a process that was inhibited by HRP, valsartan or PRR siRNA. HRP and valsartan significantly attenuated renal TGF-β1 and CTGF expression in diabetic animals and high glucose treated RMC. Similar results were observed in high glucose exposed RMC in response to PRR siRNA. TGF-β receptor blockade decreased CTGF expression in RMC. Combined administration of valsartan and PRR siRNA showed further reduction of TGF-β1 and CTGF expression in RMC. 4. In conclusion, PRR contributes to kidney disease in diabetes through an enhanced TGF-β1-CTGF signalling cascade.

  1. Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice.

    PubMed

    Inoue, Tsutomu; Okada, Hirokazu; Kobayashi, Tatsuya; Watanabe, Yusuke; Kanno, Yoshihiko; Kopp, Jeffrey B; Nishida, Takashi; Takigawa, Masaharu; Ueno, Munehisa; Nakamura, Toshikazu; Suzuki, Hiromichi

    2003-02-01

    We investigated the mechanism of the anti-fibrotic effects of hepatocyte growth factor (HGF) in the kidney, with respect to its effect on connective tissue growth factor (CTGF), a down-stream, profibrotic mediator of transforming growth factor-beta1 (TGF-beta1). In wild-type (WT) mice with 5/6 nephrectomy (Nx), HGF and TGF-beta1 mRNAs increased transiently in the remnant kidney by week 1 after the Nx, returned to baseline levels, and increased again at weeks 4 to 12. In contrast, CTGF and alpha1(I) procollagen (COLI) mRNAs increased in parallel with HGF and TGF-beta1 during the early stage, but did not re-increase during the late stage. In the case of TGF-beta1 transgenic (TG) mice with 5/6 Nx, excess TGF-beta1 derived from the transgene enhanced CTGF expression significantly in the remnant kidney, accordingly accelerating renal fibrogenesis. Administration of dHGF (5.0 mg/kg/day) to TG mice with 5/6 Nx for 4 weeks from weeks 2 to 6 suppressed CTGF expression in the remnant kidney, attenuating renal fibrosis and improving the survival rate. In an experiment in vitro, renal tubulointerstitial fibroblasts (TFB) were co-cultured with proximal tubular epithelial cells (PTEC). Pretreatment with HGF reduced significantly CTGF induction in PTEC by TGF-beta1, consequently suppressing COLI synthesis in TFB. In conclusion, HGF can block, at least partially, renal fibrogenesis promoted by TGF-beta1 in the remnant kidney, via attenuation of CTGF induction.

  2. Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β.

    PubMed

    Wang, Mei; Liu, Yang; Zou, Jiahua; Yang, Rui; Xuan, Fan; Wang, Yi; Gao, Ning; Cui, Hongjuan

    2015-04-20

    Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial event in the pathogenesis of neuroblastoma is to promote proliferation of neuroblasts, which is closely related to poor survival. However, mechanisms for regulation of cell proliferation and tumorigenicity in neuroblastoma are not well understood. Here, we report that overexpression of TAZ in neuroblastoma BE(2)-C cells causes increases in cell proliferation, self renewal and colony formation, which was restored back to its original levels by knockdown of TAZ in TAZ-overexpression cells. Inhibition of endogenous TAZ attenuated cell proliferation, colony formation and tumor development in neuroblastoma SK-N-AS cell, which could be rescued by re-introduction of TAZ into TAZ-knockdown cells. In addition, we found that overexpressing TAZ-mediated induction of CTGF and PDGF-β expression, cell proliferation and colony formation were inhibited by knocking down CTGF and PDGF-β with siRNA in TAZ-overexpressing cell. Overall, our findings suggested that TAZ plays an essential role in regulating cell proliferation and tumorigenesis in neuroblastoma cells. Thus, TAZ seems to be a novel and promising target for the treatment of neuroblastoma.

  3. Spheroid formation of human thyroid cancer cells under simulated microgravity: a possible role of CTGF and CAV1

    PubMed Central

    2014-01-01

    Background Multicellular tumor spheroids (MCTS) formed scaffold-free under microgravity are of high interest for research and medicine. Their formation mechanism can be studied in space in real microgravity or on Earth using ground-based facilities (GBF), which simulate microgravity. On Earth, these experiments are more cost-efficient and easily performable. However, each GBF might exert device-specific and altered superimposingly gravity-dependent effects on the cells. Results FTC-133 human thyroid cancer cells were cultivated on a 2D clinostat (CN) and a random positioning machine (RPM) and compared with corresponding 1 g control cells. Harvested cell samples were investigated by microscopy, quantitative realtime-PCR and Multi-Analyte Profiling. Spheroid formation and growth occurred during 72 h of cultivation on both devices. Cytokine secretion and gene activation patterns frequently altered in different ways, when the cells were cultured either on the RPM or the CN. A decreased expression of CAV1 and CTGF in MCTS compared to adherent cells was observed after cultivation on both machines. Conclusion The development of MCTS proceeds similarly on the RPM and the CN resembling the situation observed under real microgravity conditions, while no MCTS formation was observed at 1 g under identical experimental conditions. Simultaneously, changes in the regulation of CTGF and CAV1 appeared in a comparable manner on both machines. A relationship between these molecules and MCTS formation is discussed. PMID:24885050

  4. Connective tissue growth factor modulates podocyte actin cytoskeleton and extracellular matrix synthesis and is induced in podocytes upon injury.

    PubMed

    Fuchshofer, Rudolf; Ullmann, Sabrina; Zeilbeck, Ludwig F; Baumann, Matti; Junglas, Benjamin; Tamm, Ernst R

    2011-09-01

    Structural changes of podocytes and retraction of their foot processes are a critical factor in the pathogenesis of minimal change nephritis and glomerulosclerosis. Here we tested, if connective tissue growth factor (CTGF) is involved in podocyte injury during acute and chronic puromycin aminonucleoside nephrosis (PAN) as animal models of minimal change nephritis, and focal segmental glomerulosclerosis, respectively. Rats were treated once (acute PAN) or for 13 weeks (chronic PAN). In both experimental conditions, CTGF and its mRNA were found to be highly upregulated in podocytes. The upregulation correlated with onset and duration of proteinuria in acute PAN, and glomerulosclerosis and high expression of glomerular fibronectin, and collagens I, III, and IV in chronic PAN. In vitro, treatment of podocytes with recombinant CTGF increased amount and density of actin stress fibers, the expression of actin-associated molecules such as podocalyxin, synaptopodin, ezrin, and actinin-4, and activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Moreover, we observed increased podocyte expression of mRNA for transforming growth factor (TGF)-β2, TGF-β receptor II, fibronectin, and collagens I, III, and IV. Treatment of cultured podocytes with puromycin aminonucleoside resulted in loss of actin stress fibers and cell death, effects that were partially prevented when CTGF was added to the culture medium. Depletion of CTGF mRNA in cultured podocytes by RNA interference reduced both the number of actin stress fibers and the expression of actin-associated molecules. We propose that the expression of CTGF is acutely upregulated in podocytes as part of a cellular attempt to repair structural changes of the actin cytoskeleton. When the damaging effects on podocyte structure and function persist chronically, continuous CTGF expression in podocytes is a critical factor that promotes progressive accumulation of glomerular extracellular matrix and

  5. CCN3 (NOV) is a negative regulator of CCN2 (CTGF) and a novel endogenous inhibitor of the fibrotic pathway in an in vitro model of renal disease.

    PubMed

    Riser, Bruce L; Najmabadi, Feridoon; Perbal, Bernard; Peterson, Darryl R; Rambow, Jo Ann; Riser, Melisa L; Sukowski, Ernest; Yeger, Herman; Riser, Sarah C

    2009-05-01

    Fibrosis is a major cause of end-stage renal disease, and although initiation factors have been elucidated, uncertainty concerning the downstream pathways has hampered the development of anti-fibrotic therapies. CCN2 (CTGF) functions downstream of transforming growth factor (TGF)-beta, driving increased extracellular matrix (ECM) accumulation and fibrosis. We examined the possibility that CCN3 (NOV), another CCN family member with reported biological activities that differ from CCN2, might act as an endogenous negative regulator of ECM and fibrosis. We show that cultured rat mesangial cells express CCN3 mRNA and protein, and that TGF-beta treatment reduced CCN3 expression levels while increasing CCN2 and collagen type I activities. Conversely, either the addition of CCN3 or CCN3 overexpression produced a marked down-regulation of CCN2 followed by virtual blockade of both collagen type I transcription and its accumulation. This finding occurred in both growth-arrested and CCN3-transfected cells under normal growth conditions after TGF-beta treatment. These effects were not attributable to altered cellular proliferation as determined by cell cycle analysis, nor were they attributable to interference of Smad signaling as shown by analysis of phosphorylated Smad3 levels. In conclusion, both CCN2 and CCN3 appear to act in a yin/yang manner to regulate ECM metabolism. CCN3, acting downstream of TGF-beta to block CCN2 and the up-regulation of ECM, may therefore serve to naturally limit fibrosis in vivo and provide opportunities for novel, endogenous-based therapeutic treatments.

  6. Connective tissue growth factor is expressed in malignant cells of Hodgkin lymphoma but not in other mature B-cell lymphomas.

    PubMed

    Birgersdotter, Anna; Baumforth, Karl R N; Wei, Wenbin; Murray, Paul G; Sjöberg, Jan; Björkholm, Magnus; Porwit, Anna; Ernberg, Ingemar

    2010-02-01

    Connective tissue growth factor (CTGF) has a major role in development of fibrosis and in the wound-healing process. Microarray analysis of 44 classical Hodgkin lymphoma (cHL) samples showed higher CTGF messenger RNA expression in the nodular sclerosis (NS) than in the mixed cellularity (MC) subtype. When analyzed by immunohistochemical analysis, Hodgkin-Reed-Sternberg (H-RS) cells and macrophages in 23 cHLs and "popcorn" cells in 2 nodular lymphocyte predominant Hodgkin lymphomas showed expression of CTGF protein correlating with the extent of fibrosis. In NS, CTGF was also expressed in fibroblasts and occasional lymphocytes. Malignant cells in 32 samples of various non-Hodgkin lymphomas were negative for CTGF. A staining pattern of stromal cells similar to that of NS cHL was seen in anaplastic large cell lymphoma. Macrophages stained positively in Burkitt lymphomas and in some mantle cell lymphomas. The high occurrence of fibrosis in cHL may be related to CTGF expression by malignant H-RS cells.

  7. Downregulation of Connective Tissue Growth Factor by Three-Dimensional Matrix Enhances Ovarian Carcinoma Cell Invasion

    PubMed Central

    Barbolina, Maria V.; Adley, Brian P.; Kelly, David L.; Shepard, Jaclyn; Fought, Angela J.; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D.; Sharon Stack, M

    2010-01-01

    Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancy, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intra-peritoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hours of 3-dimensional collagen culture) coupled with confirmatory real-time RT-PCR, multiple three-dimensional cell culture matrices, Western blot, immunostaining, adhesion, migration, and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion-mimicking conditions (3-dimensional type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n=41), but was present in 100% of normal ovarian epithelium samples (n=7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced, collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using α6β1 and α3β1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion. PMID:19382180

  8. Downregulation of connective tissue growth factor by three-dimensional matrix enhances ovarian carcinoma cell invasion.

    PubMed

    Barbolina, Maria V; Adley, Brian P; Kelly, David L; Shepard, Jaclyn; Fought, Angela J; Scholtens, Denise; Penzes, Peter; Shea, Lonnie D; Stack, M Sharon

    2009-08-15

    Epithelial ovarian carcinoma (EOC) is a leading cause of death from gynecologic malignancies, due mainly to the prevalence of undetected metastatic disease. The process of cell invasion during intraperitoneal anchoring of metastatic lesions requires concerted regulation of many processes, including modulation of adhesion to the extracellular matrix and localized invasion. Exploratory cDNA microarray analysis of early response genes (altered after 4 hr of 3D collagen culture) coupled with confirmatory real-time reverse-transcriptase polymerase chain reaction, multiple 3D cell culture matrices, Western blot, immunostaining, adhesion, migration and invasion assays were used to identify modulators of adhesion pertinent to EOC progression and metastasis. cDNA microarray analysis indicated a dramatic downregulation of connective tissue growth factor (CTGF) in EOC cells placed in invasion- mimicking conditions (3D Type I collagen). Examination of human EOC specimens revealed that CTGF expression was absent in 46% of the tested samples (n = 41), but was present in 100% of normal ovarian epithelium samples (n = 7). Reduced CTGF expression occurs in many types of cells and may be a general phenomenon displayed by cells encountering a 3D environment. CTGF levels were inversely correlated with invasion such that downregulation of CTGF increased, while its upregulation reduced collagen invasion. Cells adhered preferentially to a surface comprised of both collagen I and CTGF relative to either component alone using alpha6beta1 and alpha3beta1 integrins. Together these data suggest that downregulation of CTGF in EOC cells may be important for cell invasion through modulation of cell-matrix adhesion.

  9. Matrix Metalloproteinase-2-deficient Fibroblasts Exhibit an Alteration in the Fibrotic Response to Connective Tissue Growth Factor/CCN2 because of an Increase in the Levels of Endogenous Fibronectin*

    PubMed Central

    Droppelmann, Cristian A.; Gutiérrez, Jaime; Vial, Cecilia; Brandan, Enrique

    2009-01-01

    Matrix metalloproteinase-2 (MMP-2) is an important extracellular matrix remodeling enzyme, and it has been involved in different fibrotic disorders. The connective tissue growth factor (CTGF/CCN2), which is increased in these pathologies, induces the production of extracellular matrix proteins. To understand the fibrotic process observed in diverse pathologies, we analyzed the fibroblast response to CTGF when MMP-2 activity is inhibited. CTGF increased fibronectin (FN) amount, MMP-2 mRNA expression, and gelatinase activity in 3T3 cells. When MMP-2 activity was inhibited either by the metalloproteinase inhibitor GM-6001 or in MMP-2-deficient fibroblasts, an increase in the basal amount of FN together with a decrease of its levels in response to CTGF was observed. This paradoxical effect could be explained by the fact that the excess of FN could block the access to other ligands, such as CTGF, to integrins. This effect was emulated in fibroblasts by adding exogenous FN or RGDS peptides or using anti-integrin αV subunit-blocking antibodies. Additionally, in MMP-2-deficient cells CTGF did not induce the formation of stress fibers, focal adhesion sites, and ERK phosphorylation. Anti-integrin αV subunit-blocking antibodies inhibited ERK phosphorylation in control cells. Finally, in MMP-2-deficient cells, FN mRNA expression was not affected by CTGF, but degradation of 125I-FN was increased. These results suggest that expression, regulation, and activity of MMP-2 can play an important role in the initial steps of fibrosis and shows that FN levels can regulate the cellular response to CTGF. PMID:19276073

  10. Induction of Connective Tissue Growth Factor Expression by Hypoxia in Human Lung Fibroblasts via the MEKK1/MEK1/ERK1/GLI-1/GLI-2 and AP-1 Pathways

    PubMed Central

    Cheng, Yi; Lin, Chien-huang; Chen, Jing-Yun; Li, Chien-Hua; Liu, Yu-Tin; Chen, Bing-Chang

    2016-01-01

    Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time-dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF-luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF-luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c-Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in α-smooth muscle actin (α-SMA) and collagen production, which was blocked by GLI-1 siRNA and

  11. CXCL12 induces connective tissue growth factor expression in human lung fibroblasts through the Rac1/ERK, JNK, and AP-1 pathways.

    PubMed

    Lin, Chien-Huang; Shih, Chung-Huang; Tseng, Chih-Chieh; Yu, Chung-Chi; Tsai, Yuan-Jhih; Bien, Mauo-Ying; Chen, Bing-Chang

    2014-01-01

    CXCL12 (stromal cell-derived factor-1, SDF-1) is a potent chemokine for homing of CXCR4+ fibrocytes to injury sites of lung tissue, which contributes to pulmonary fibrosis. Overexpression of connective tissue growth factor (CTGF) plays a critical role in pulmonary fibrosis. In this study, we investigated the roles of Rac1, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CXCL12-induced CTGF expression in human lung fibroblasts. CXCL12 caused concentration- and time-dependent increases in CTGF expression and CTGF-luciferase activity. CXCL12-induced CTGF expression was inhibited by a CXCR4 antagonist (AMD3100), small interfering RNA of CXCR4 (CXCR4 siRNA), a dominant negative mutant of Rac1 (RacN17), a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor (PD98059), a JNK inhibitor (SP600125), a p21-activated kinase inhibitor (PAK18), c-Jun siRNA, and an AP-1 inhibitor (curcumin). Treatment of cells with CXCL12 caused activations of Rac1, Rho, ERK, and c-Jun. The CXCL12-induced increase in ERK phosphorylation was inhibited by RacN17. Treatment of cells with PD98059 and SP600125 both inhibited CXCL12-induced c-Jun phosphorylation. CXCL12 caused the recruitment of c-Jun and c-Fos binding to the CTGF promoter. Furthermore, CXCL12 induced an increase in α-smooth muscle actin (α-SMA) expression, a myofibroblastic phenotype, and actin stress fiber formation. CXCL12-induced actin stress fiber formation and α-SMA expression were respectively inhibited by AMD3100 and CTGF siRNA. Taken together, our results suggest that CXCL12, acting through CXCR4, activates the Rac/ERK and JNK signaling pathways, which in turn initiates c-Jun phosphorylation, and recruits c-Jun and c-Fos to the CTGF promoter and ultimately induces CTGF expression in human lung fibroblasts. Moreover, overexpression of CTGF mediates CXCL12-induced α-SMA expression.

  12. CXCL12 Induces Connective Tissue Growth Factor Expression in Human Lung Fibroblasts through the Rac1/ERK, JNK, and AP-1 Pathways

    PubMed Central

    Tseng, Chih-Chieh; Yu, Chung-Chi; Tsai, Yuan-Jhih; Bien, Mauo-Ying; Chen, Bing-Chang

    2014-01-01

    CXCL12 (stromal cell-derived factor-1, SDF-1) is a potent chemokine for homing of CXCR4+ fibrocytes to injury sites of lung tissue, which contributes to pulmonary fibrosis. Overexpression of connective tissue growth factor (CTGF) plays a critical role in pulmonary fibrosis. In this study, we investigated the roles of Rac1, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CXCL12-induced CTGF expression in human lung fibroblasts. CXCL12 caused concentration- and time-dependent increases in CTGF expression and CTGF-luciferase activity. CXCL12-induced CTGF expression was inhibited by a CXCR4 antagonist (AMD3100), small interfering RNA of CXCR4 (CXCR4 siRNA), a dominant negative mutant of Rac1 (RacN17), a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor (PD98059), a JNK inhibitor (SP600125), a p21-activated kinase inhibitor (PAK18), c-Jun siRNA, and an AP-1 inhibitor (curcumin). Treatment of cells with CXCL12 caused activations of Rac1, Rho, ERK, and c-Jun. The CXCL12-induced increase in ERK phosphorylation was inhibited by RacN17. Treatment of cells with PD98059 and SP600125 both inhibited CXCL12-induced c-Jun phosphorylation. CXCL12 caused the recruitment of c-Jun and c-Fos binding to the CTGF promoter. Furthermore, CXCL12 induced an increase in α-smooth muscle actin (α-SMA) expression, a myofibroblastic phenotype, and actin stress fiber formation. CXCL12-induced actin stress fiber formation and α-SMA expression were respectively inhibited by AMD3100 and CTGF siRNA. Taken together, our results suggest that CXCL12, acting through CXCR4, activates the Rac/ERK and JNK signaling pathways, which in turn initiates c-Jun phosphorylation, and recruits c-Jun and c-Fos to the CTGF promoter and ultimately induces CTGF expression in human lung fibroblasts. Moreover, overexpression of CTGF mediates CXCL12-induced α-SMA expression. PMID:25121739

  13. Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells

    SciTech Connect

    Matsuzaki, Shinichi; Ishizuka, Tamotsu; Yamada, Hidenori; Kamide, Yosuke; Hisada, Takeshi; Ichimonji, Isao; Aoki, Haruka; Yatomi, Masakiyo; Komachi, Mayumi; Tsurumaki, Hiroaki; Ono, Akihiro; Koga, Yasuhiko; Dobashi, Kunio; Mogi, Chihiro; Sato, Koichi; Tomura, Hideaki; Mori, Masatomo; Okajima, Fumikazu

    2011-10-07

    Highlights: {yields} The involvement of extracellular acidification in airway remodeling was investigated. {yields} Extracellular acidification alone induced CTGF production in human ASMCs. {yields} Extracellular acidification enhanced TGF-{beta}-induced CTGF production in human ASMCs. {yields} Proton-sensing receptor OGR1 was involved in acidic pH-stimulated CTGF production. {yields} OGR1 may play an important role in airway remodeling in asthma. -- Abstract: Asthma is characterized by airway inflammation, hyper-responsiveness and remodeling. Extracellular acidification is known to be associated with severe asthma; however, the role of extracellular acidification in airway remodeling remains elusive. In the present study, the effects of acidification on the expression of connective tissue growth factor (CTGF), a critical factor involved in the formation of extracellular matrix proteins and hence airway remodeling, were examined in human airway smooth muscle cells (ASMCs). Acidic pH alone induced a substantial production of CTGF, and enhanced transforming growth factor (TGF)-{beta}-induced CTGF mRNA and protein expression. The extracellular acidic pH-induced effects were inhibited by knockdown of a proton-sensing ovarian cancer G-protein-coupled receptor (OGR1) with its specific small interfering RNA and by addition of the G{sub q/11} protein-specific inhibitor, YM-254890, or the inositol-1,4,5-trisphosphate (IP{sub 3}) receptor antagonist, 2-APB. In conclusion, extracellular acidification induces CTGF production through the OGR1/G{sub q/11} protein and inositol-1,4,5-trisphosphate-induced Ca{sup 2+} mobilization in human ASMCs.

  14. Connective tissue growth factor production by activated pancreatic stellate cells in mouse alcoholic chronic pancreatitis

    PubMed Central

    Charrier, Alyssa; Brigstock, David R.

    2010-01-01

    Alcoholic chronic pancreatitis (ACP) is characterized by pancreatic necrosis, inflammation, and scarring, the latter of which is due to excessive collagen deposition by activated pancreatic stellate cells (PSC). The aim of this study was to establish a model of ACP in mice, a species that is usually resistant to the toxic effects of alcohol, and to identify the cell type(s) responsible for production of connective tissue growth factor (CTGF), a pro-fibrotic molecule. C57Bl/6 male mice received intraperitoneal ethanol injections for three weeks against a background of cerulein-induced acute pancreatitis. Peak blood alcohol levels remained consistently high in ethanol-treated mice as compared to control mice. In mice receiving ethanol plus cerulein, there was increased collagen deposition as compared to other treatment groups as well as increased frequency of α-smooth muscle actin and desmin-positive PSC which also demonstrated significantly enhanced CTGF protein production. Expression of mRNA for collagen α1(I), α-smooth muscle actin or CTGF were all increased and co-localized exclusively to activated PSC in ACP. Pancreatic expression of mRNA for key profibrotic markers were all increased in ACP. In conclusion, a mouse model of ACP has been developed that mimics key pathophysiological features of the disease in humans and which shows that activated PSC are the principal producers of collagen and CTGF. PSC-derived CTGF is thus a candidate therapeutic target in anti-fibrotic strategies for ACP. PMID:20368699

  15. High expression of connective tissue growth factor in pre-B acute lymphoblastic leukaemia.

    PubMed

    Boag, Joanne M; Beesley, Alex H; Firth, Martin J; Freitas, Joseph R; Ford, Jette; Brigstock, David R; de Klerk, Nicholas H; Kees, Ursula R

    2007-09-01

    In recent years microarrays have been used extensively to characterize gene expression in acute lymphoblastic leukaemia (ALL). Few studies, however, have analysed normal haematopoietic cell populations to identify altered gene expression in ALL. We used oligonucleotide microarrays to compare the gene expression profile of paediatric precursor-B (pre-B) ALL specimens with two control cell populations, normal CD34(+) and CD19(+)IgM(-) cells, to focus on genes linked to leukemogenesis. A set of eight genes was identified with a ninefold higher average expression in ALL specimens compared with control cells. All of these genes were significantly deregulated in an independent cohort of 101 ALL specimens. One gene, connective tissue growth factor (CTGF, also known as CCN2), had exceptionally high expression, which was confirmed in three independent leukaemia studies. Further analysis of CTGF expression in ALL revealed exclusive expression in B-lineage, not T-lineage, ALL. Within B-lineage ALL approximately 75% of specimens were consistently positive for CTGF expression, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies using Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. These findings indicate that CTGF is secreted by pre-B ALL cells and may play a role in the pathophysiology of this disease.

  16. Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients

    PubMed Central

    Stratton, Richard; Shiwen, Xu; Martini, Giorgia; Holmes, Alan; Leask, Andrew; Haberberger, Thomas; Martin, George R.; Black, Carol M.; Abraham, David

    2001-01-01

    Patients with scleroderma receiving Iloprost as a treatment for severe Raynaud’s phenomenon report a reduction in skin tightness, suggesting that this drug inhibits skin fibrosis. Connective tissue growth factor (CTGF), a recently described profibrotic cytokine, acts downstream and in concert with TGF-β to stimulate the fibrotic process and is involved in the fibrosis seen in scleroderma. Here we show that Iloprost, acting by elevation of cAMP, blocks the induction of CTGF and the increase in collagen synthesis in fibroblasts exposed to TGF-β. The potency of Iloprost with respect to suppression of CTGF far exceeds that of other prostanoid receptor agonists, suggesting that its effect is mediated by the prostacyclin receptor IP. By sampling dermal interstitial fluid using a suction blister device, we show that CTGF levels are greatly elevated in the dermis of scleroderma patients compared with healthy controls and that Iloprost infusion causes a marked decrease in dermal CTGF levels. These studies suggest that Iloprost could be reducing the level of a key profibrotic cytokine in scleroderma patients and that endogenous production of eicosanoids may limit the fibrotic response to TGF-β. PMID:11457877

  17. Connective tissue growth factor is involved in structural retinal vascular changes in long-term experimental diabetes.

    PubMed

    Van Geest, Rob J; Leeuwis, Jan Willem; Dendooven, Amélie; Pfister, Frederick; Bosch, Klazien; Hoeben, Kees A; Vogels, Ilse M C; Van der Giezen, Dionne M; Dietrich, Nadine; Hammes, Hans-Peter; Goldschmeding, Roel; Klaassen, Ingeborg; Van Noorden, Cornelis J F; Schlingemann, Reinier O

    2014-02-01

    Early retinal vascular changes in the development of diabetic retinopathy (DR) include capillary basal lamina (BL) thickening, pericyte loss and the development of acellular capillaries. Expression of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family member CCN2 or connective tissue growth factor (CTGF), a potent inducer of the expression of BL components, is upregulated early in diabetes. Diabetic mice lacking one functional CTGF allele (CTGF⁺/⁻) do not show this BL thickening. As early events in DR may be interrelated, we hypothesized that CTGF plays a role in the pathological changes of retinal capillaries other than BL thickening. We studied the effects of long-term (6-8 months) streptozotocin-induced diabetes on retinal capillary BL thickness, numbers of pericytes and the development of acellular capillaries in wild type and CTGF⁺/⁻ mice. Our results show that an absence of BL thickening of retinal capillaries in long-term diabetic CTGF⁺/⁻ mice is associated with reduced pericyte dropout and reduced formation of acellular capillaries. We conclude that CTGF is involved in structural retinal vascular changes in diabetic rodents. Inhibition of CTGF in the eye may therefore be protective against the development of DR.

  18. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

    SciTech Connect

    Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun Nishina, Hiroshi

    2014-01-17

    Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP’s functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP’s co-activation of TEAD-mediated CTGF transcription.

  19. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity.

    PubMed

    Shimomura, Tadanori; Miyamura, Norio; Hata, Shoji; Miura, Ryota; Hirayama, Jun; Nishina, Hiroshi

    2014-01-17

    YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP's functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP's co-activation of TEAD-mediated CTGF transcription.

  20. Rapamycin regulates connective tissue growth factor expression of lung epithelial cells via phosphoinositide 3-kinase.

    PubMed

    Xu, Xuefeng; Wan, Xuan; Geng, Jing; Li, Fei; Yang, Ting; Dai, Huaping

    2013-09-01

    The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains largely unknown. It is believed that IPF is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances (such as connective tissue growth factor, CTGF) that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and CTGF expression. Transformed epithelial cell line A549 and normal human pulmonary alveolar or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine CTGF mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting CTGF protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor (TGF)-β type I receptor (TβRI) inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or TGF-β1 induced CTGF expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on CTGF expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human lung fibrosis.

  1. "La CLAve" to Increase Psychosis Literacy of Spanish-Speaking Community Residents and Family Caregivers

    ERIC Educational Resources Information Center

    Lopez, Steven R.; Lara, Ma. Del Carmen; Kopelowicz, Alex; Solano, Susana; Foncerrada, Hector; Aguilera, Adrian

    2009-01-01

    The authors developed and tested a 35-min psychoeducational program with the goal of increasing Spanish-speaking persons' literacy of psychosis. The program uses popular cultural icons derived from music, art, and videos, as well as a mnemonic device--La CLAve (The Clue)--to increase (a) knowledge of psychosis, (b) efficacy beliefs that one can…

  2. Transforming growth factor-β (TGF-β) expression is increased in the subsynovial connective tissue in a rabbit model of carpal tunnel syndrome.

    PubMed

    Chikenji, Takako; Gingery, Anne; Zhao, Chunfeng; Vanhees, Matthias; Moriya, Tamami; Reisdorf, Ramona; An, Kai-Nan; Amadio, Peter C

    2014-01-01

    Carpal tunnel syndrome (CTS) is an idiopathic disease that results from increased fibrosis of the subsynovial connective tissue (SSCT). A recent study found overexpression of both transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) in the SSCT of CTS patients. This study investigated TGF-β and CTGF expression in a rabbit model of CTS, in which SSCT fibrosis is induced by a surgical injury. Levels of TGF-β1 and CTGF at 6, 12, 24 weeks after injury were determined by immunohistochemistry A significant increase in TGF-β1 and a concomitant significant increase in CTGF were found at 6 weeks, in addition to higher cell density compared to normal (all p<0.05), Interestingly, CTGF expression was reduced at 12 and 24 weeks, suggesting that an initial insult results in a time limited response. We conclude that this rabbit model mimics the fibrosis found in human CTS, and may be useful to study pathogenetic mechanisms of CTS in vivo.

  3. Transforming growth factor-β (TGF-β) expression is increased in the subsynovial connective tissues of patients with idiopathic carpal tunnel syndrome.

    PubMed

    Chikenji, Takako; Gingery, Anne; Zhao, Chunfeng; Passe, Sandra M; Ozasa, Yasuhiro; Larson, Dirk; An, Kai-Nan; Amadio, Peter C

    2014-01-01

    Non-inflammatory fibrosis of the subsynovial connective tissue (SSCT) is a hallmark of carpal tunnel syndrome (CTS). The etiology of this finding and its relationship to the development of CTS remain poorly understood. Recent studies have found that transforming growth factor-β (TGF-β) plays a central role in fibrosis. The purpose of this study was to investigate the expression of TGF-β and connective tissue growth factor (CTGF), a downstream mediator of TGF-β, in the pathogenesis of CTS. We compared SSCT specimens from 26 idiopathic CTS patients with specimens from 10 human cadaver controls with no previous diagnosis of CTS. Immunohistochemistry was performed to determine levels TGF-β1, CTGF, collagen 1(Col1) and collagen 3 (Col3) expression. TGF-β1 (p < 0.01), CTGF (p < 0.01), and Col3 (p < 0.01) were increased in SSCT of CTS patients compared with control tissue. In addition, a strong positive correlation was found between TGF-β1 and CTGF, (R(2) = 0.80, p < 0.01) and a moderate positive correlation between Col3 and TGF-β1 (R(2) = 0.49, p < 0.01). These finding suggest that there is an increased expression of TGF-β and CTGF, a TGF-β regulated protein, and that this TGF-β activation may be responsible for SSCT fibrosis in CTS patients.

  4. A soluble factor from Trypanosoma cruzi inhibits transforming growth factor-ß-induced MAP kinase activation and gene expression in dermal fibroblasts.

    PubMed

    Mott, G Adam; Costales, Jaime A; Burleigh, Barbara A

    2011-01-01

    The protozoan parasite Trypanosoma cruzi, which causes human Chagas' disease, exerts a variety of effects on host extracellular matrix (ECM) including proteolytic degradation of collagens and dampening of ECM gene expression. Exposure of primary human dermal fibroblasts to live infective T. cruzi trypomastigotes or their shed/secreted products results in a rapid down-regulation of the fibrogenic genes collagenIα1, fibronectin and connective tissue growth factor (CTGF/CCN2). Here we demonstrate the ability of a secreted/released T. cruzi factor to antagonize ctgf/ccn2 expression in dermal fibroblasts in response to TGF-ß, lysophosphatidic acid or serum, where agonist-induced phosphorylation of the mitogen-activated protein (MAP) kinases Erk1/2, p38 and JNK was also inhibited. Global analysis of gene expression in dermal fibroblasts identified a discrete subset of TGF-ß-inducible genes involved in cell proliferation, wound repair, and immune regulation that are inhibited by T. cruzi secreted/released factors, where the genes exhibiting the highest sensitivity to T. cruzi are known to be regulated by MAP kinase-activated transcription factors. Consistent with this observation, the Ets-family transcription factor binding site in the proximal promoter region of the ctgf/ccn2 gene (-91 bp to -84 bp) was shown to be required for T. cruzi-mediated down-regulation of ctgf/ccn2 reporter expression. The cumulative data suggest a model in which T. cruzi-derived molecules secreted/released early in the infective process dampen MAP kinase signaling and the activation of transcription factors that regulate expression of fibroblast genes involved in wound repair and tissue remodelling, including ctgf/ccn2. These findings have broader implications for local modulation of ECM synthesis/remodelling by T. cruzi during the early establishment of infection in the mammalian host and highlight the potential for pathogen-derived molecules to be exploited as tools to modulate the

  5. Potential Therapeutic Targets for Oral Cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70

    PubMed Central

    Bundela, Saurabh; Sharma, Anjana; Bisen, Prakash S.

    2014-01-01

    In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL-10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70. PMID:25029526

  6. VRP09 Reduction of Corneal Scarring Following Blast and Burn Injuries to Cornea Using siRNAs Targeting TGFb and CTGF

    DTIC Science & Technology

    2013-03-01

    aSMA ) synthesis. Second, we proposed to develop an advanced ex vivo organ culture system using viable explants of rabbit corneas, and assess the...effect of the most effective triple siRNA combination for reduction of target genes, collagen and alpha smooth muscle actin ( aSMA ) in rabbit corneas...targeting three key genes (TGFb, TGFbRII, and CTGF) that synergistically reduces the level of mRNAs for type I collagen gene and aSMA by >95% without

  7. miR-29b promotes skin wound healing and reduces excessive scar formation by inhibition of the TGF-β1/Smad/CTGF signaling pathway.

    PubMed

    Guo, Jingdong; Lin, Quan; Shao, Ying; Rong, Li; Zhang, Duo

    2017-04-01

    The hypertrophic scar is a medical difficulty of humans, which has caused great pain to patients. Here, we investigated the inhibitory effect of miR-29b on scar formation. The scalded model was established in mice and miR-29b mimics or a negative control was subcutaneously injected into the injury skin. Then various molecular biological experiments were performed to assess the effect of miR-29b on scar formation. According to our present study, first, the results demonstrated that miR-29b was down-regulated in thermal injury tissue and miR-29b treatment could promote wound healing, inhibit scar formation, and alleviate histopathological morphologic alteration in scald tissues. Additionally, miR-29b treatment suppressed collagen deposition and fibrotic gene expression in scar tissues. Finally, we found that miR-29b treatment inhibited the TGF-β1/Smad/CTGF signaling pathway. Taken together, our data suggest that miR-29b treatment has an inhibitory effect against scar formation via inhibition of the TGF-β1/Smad/CTGF signaling pathway and may provide a potential molecular basis for future treatments for hypertrophic scars.

  8. Cucurbitacin I Attenuates Cardiomyocyte Hypertrophy via Inhibition of Connective Tissue Growth Factor (CCN2) and TGF- β/Smads Signalings

    PubMed Central

    Kang, Hara; Park, Kye Won; Park, Woo Jin; Yang, Seung Yul; Yang, Dong Kwon

    2015-01-01

    Cucurbitacin I is a naturally occurring triterpenoid derived from Cucurbitaceae family plants that exhibits a number of potentially useful pharmacological and biological activities. However, the therapeutic impact of cucurbitacin I on the heart has not heretofore been reported. To evaluate the functional role of cucurbitacin I in an in vitro model of cardiac hypertrophy, phenylephrine (PE)-stimulated cardiomyocytes were treated with a sub-cytotoxic concentration of the compound, and the effects on cell size and mRNA expression levels of ANF and β-MHC were investigated. Consequently, PE-induced cell enlargement and upregulation of ANF and β-MHC were significantly suppressed by pretreatment of the cardiomyocytes with cucurbitacin I. Notably, cucurbitacin I also impaired connective tissue growth factor (CTGF) and MAPK signaling, pro-hypertrophic factors, as well as TGF-β/Smad signaling, the important contributing factors to fibrosis. The protective impact of cucurbitacin I was significantly blunted in CTGF-silenced or TGF-β1-silenced hypertrophic cardiomyocytes, indicating that the compound exerts its beneficial actions through CTGF. Taken together, these findings signify that cucurbitacin I protects the heart against cardiac hypertrophy via inhibition of CTGF/MAPK, and TGF- β/Smad-facilitated events. Accordingly, the present study provides new insights into the defensive capacity of cucurbitacin I against cardiac hypertrophy, and further suggesting cucurbitacin I’s utility as a novel therapeutic agent for the management of heart diseases. PMID:26296085

  9. Connective tissue growth factor is not necessary for haze formation in excimer laser wounded mouse corneas

    PubMed Central

    Feng, Xiaodi; Pi, Liya; Sriram, Sriniwas; Schultz, Gregory S.

    2017-01-01

    We sought to determine if connective tissue growth factor (CTGF) is necessary for the formation of corneal haze after corneal injury. Mice with post-natal, tamoxifen-induced, knockout of CTGF were subjected to excimer laser phototherapeutic keratectomy (PTK) and the corneas were allowed to heal. The extent of scaring was observed in non-induced mice, heterozygotes, and full homozygous knockout mice and quantified by macrophotography. The eyes from these mice were collected after euthanization for re-genotyping to control for possible Cre-mosaicism. Primary corneal fibroblasts from CTGF knockout corneas were established in a gel plug assay. The plug was removed, simulating an injury, and the rate of hole closure and the capacity for these cells to form light reflecting cells in response to CTGF and platelet-derived growth factor B (PDGF-B) were tested and compared to wild-type cells. We found that independent of genotype, each group of mice was still capable of forming light reflecting haze in the cornea after laser ablation (p = 0.40). Results from the gel plug closure rate in primary cell cultures of knockout cells were not statistically different from serum starved wild-type cells, independent of treatment. Compared to the serum starved wild-type cells, stimulation with PDGF-BB significantly increased the KO cell culture’s light reflection (p = 0.03). Most interestingly, both reflective cultures were positive for α-SMA, but the cellular morphology and levels of α-SMA were distinct and not in proportion to the light reflection seen. This new work demonstrates that corneas without CTGF can still form sub-epithelial haze, and that the light reflecting phenotype can be reproduced in culture. These data support the possibilities of growth factor redundancy and that multiple pro-haze pathways exist. PMID:28207886

  10. Hammerhead Ribozyme-Mediated Knockdown of mRNA for Fibrotic Growth Factors: Transforming Growth Factor-Beta 1 and Connective Tissue Growth Factor

    PubMed Central

    Robinson, Paulette M.; Blalock, Timothy D.; Yuan, Rong; Lewin, Alfred S.; Schultz, Gregory S.

    2013-01-01

    Excessive scarring (fibrosis) is a major cause of pathologies in multiple tissues, including lung, liver, kidney, heart, cornea, and skin. The transforming growth factor- β (TGF- β) system has been shown to play a key role in regulating the formation of scar tissue throughout the body. Furthermore, connective tissue growth factor (CTGF) has been shown to mediate most of the fibrotic actions of TGF- β, including stimulation of synthesis of extracellular matrix and differentiation of fibroblasts into myofibroblasts. Currently, no approved drugs selectively and specifically regulate scar formation. Thus, there is a need for a drug that selectively targets the TGF- β cascade at the molecular level and has minimal off-target side effects. This chapter focuses on the design of hammerhead ribozymes, measurement of kinetic activity, and assessment of knockdown mRNAs of TGF- β and CTGF in cell cultures. PMID:22131029

  11. La CLAve to Increase Psychosis Literacy of Spanish-Speaking Community Residents and Family Caregivers

    PubMed Central

    López, Steven R.; Kopelowicz, Alex; Solano, Susana; del Carmen Lara, Ma.; Foncerrada, Hector; Aguilera, Adrian

    2014-01-01

    The authors developed and tested a 35-min psychoeducational program with the goal of increasing Spanish-speaking persons’ literacy of psychosis. The program uses popular cultural icons derived from music, art, and videos, as well as a mnemonic device—La CLAve (The Clue)—to increase (a) knowledge of psychosis, (b) efficacy beliefs that one can identify psychosis in others, (c) attributions to mental illness, and (d) professional help-seeking. Assessments were conducted before and after administering the program to both community residents (n = 57) and family caregivers of persons with schizophrenia (n = 38). For community residents, the authors observed increases across the 4 domains of symptom knowledge, efficacy beliefs, illness attributions, and recommended help-seeking. For caregivers, increases were observed in symptom knowledge and efficacy beliefs. La CLAve is a conceptually informed psychoeducational tool with a developing empirical base aimed at helping Spanish-speaking Latinos with serious mental illness obtain care in a timely manner. PMID:19634968

  12. Activation of PPAR-γ inhibits differentiation of rat osteoblasts by reducing expression of connective tissue growth factor.

    PubMed

    Yu, Wei-Wei; Xia, Qin; Wu, Yan; Bu, Qiao-Yun

    2014-10-01

    Long-term treatment with an agonist of peroxisome proliferator-activated receptor (PPAR)-γ is associated with bone fractures in the clinical practice. However, the mechanisms underlying the fractures are not fully understood. This study was aimed to examine the effect of rosiglitazone (an agonist of PPAR-γ) of different doses on the proliferation, differentiation, and transforming growth factor beta 1 (TGF-β1)-induced expression of connective tissue growth factor (CTGF) in primary rat osteoblasts in vitro. Osteoblasts were isolated from newly born SD rats and treated with different doses of rosiglitazone (0-20 μmol/L). The proliferation and differentiation of osteoblasts were measured by MTT assay and NPP assay, respectively. The expression of CTGF was determined by RT-PCR and Western blotting. The results showed that most isolated osteoblasts displayed strong alkaline phosphatase (ALP) activity and treatment with different doses of rosiglitazone did not affect their proliferation, but significantly inhibited the differentiation of osteoblasts in a dose-dependent manner. Moreover, treatment with different doses of rosiglitazone significantly reduced the TGF-β1-induced CTGF mRNA transcription and protein expression in a dose-dependent manner in rat osteoblasts. It was concluded that the activation of PPAR-γ may inhibit the differentiation of osteoblasts by reducing the TGF-β1-induced CTGF expression in vitro.

  13. CLAVE: Revista Especializada de ASOVELE (Asociacion Venezolana para la Ensenanza de la Lengua), 1997-1998 (CLAVE: Specialized Magazine of ASOVELE [Venezuelan Association for Language Teaching], 1997-1998).

    ERIC Educational Resources Information Center

    Rondon, Adolfo, Ed.; Serron, Sergio, Ed.

    1998-01-01

    These two issues of the journal "CLAVE" contain these articles in Spanish with one article in English: "La ensenanza de la lingua materna" (Pablo Arnaez); "Saben resumir los alumnos universitarios de nuevo ingreso?" (Marisol Garcia); "El desempeno en la escritura de cartas argumentativas y cuentos en alumnos de octavo grado" (Yolanda Perez, Maria…

  14. CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts

    PubMed Central

    Tang, Chun-Mei; Zhang, Ming; Huang, Lei; Hu, Zhi-qin; Zhu, Jie-Ning; Xiao, Zhen; Zhang, Zhuo; Lin, Qiu-xiong; Zheng, Xi-Long; -Yang, Min; Wu, Shu-Lin; Cheng, Jian-Ding; Shan, Zhi-Xin

    2017-01-01

    Circular RNAs (circRNAs) participate in regulating gene expression in diverse biological and pathological processes. The present study aimed to investigate the mechanism underlying the modulation of circRNA_000203 on expressions of fibrosis-associated genes in cardiac fibroblasts. CircRNA_000203 was shown upregulated in the diabetic mouse myocardium and in Ang-II-induced mouse cardiac fibroblasts. Enforced-expression of circRNA_000203 could increase expressions of Col1a2, Col3a1 and α-SMA in mouse cardiac fibroblasts. RNA pull-down and RT-qPCR assay indicated that circRNA_000203 could specifically sponge miR-26b-5p. Dual luciferase reporter assay revealed that miR-26b-5p interacted with 3′UTRs of Col1a2 and CTGF, and circ_000203 could block the interactions of miR-26b-5p and 3′UTRs of Col1a2 and CTGF. Transfection of miR-26b-5p could post-transcriptionaly inhibit expressions of Col1a2 and CTGF, accompanied with the suppressions of Col3a1 and α-SMA in cardiac fibroblasts. Additionally, over-expression of circRNA_000203 could eliminate the anti-fibrosis effect of miR-26b-5p in cardiac fibroblasts. Together, our results reveal that suppressing the function of miR-26b-5p contributes to the pro-fibrosis effect of circRNA_000203 in cardiac fibroblasts. PMID:28079129

  15. Recombinant Expression, Purification, and Functional Characterisation of Connective Tissue Growth Factor and Nephroblastoma-Overexpressed Protein

    PubMed Central

    Bohr, Wilhelm; Kupper, Michael; Hoffmann, Kurt; Weiskirchen, Ralf

    2010-01-01

    The CCN family of proteins, especially its prominent member, the Connective tissue growth factor (CTGF/CCN2) has been identified as a possible biomarker for the diagnosis of fibrotic diseases. As a downstream mediator of TGF-β1 signalling, it is involved in tissue scarring, stimulates interstitial deposition of extracellular matrix proteins, and promotes proliferation of several cell types. Another member of this family, the Nephroblastoma-Overexpressed protein (NOV/CCN3), has growth-inhibiting properties. First reports further suggest that these two CCN family members act opposite to each other in regulating extracellular matrix protein expression and reciprocally influence their own expression when over-expressed. We have established stable HEK and Flp-In-293 clones as productive sources for recombinant human CCN2/CTGF. In addition, we generated an adenoviral vector for recombinant expression of rat NOV and established protocols to purify large quantities of these CCN proteins. The identity of purified human CCN2/CTGF and rat CCN3/NOV was proven by In-gel digest followed by ESI-TOF/MS mass spectrometry. The biological activity of purified proteins was demonstrated using a Smad3-sensitive reporter gene and BrdU proliferation assay in permanent cell line EA•hy 926 cells. We further demonstrate for the first time that both recombinant CCN proteins are N-glycosylated. PMID:21209863

  16. l-Theanine prevents carbon tetrachloride-induced liver fibrosis via inhibition of nuclear factor κB and down-regulation of transforming growth factor β and connective tissue growth factor.

    PubMed

    Pérez-Vargas, J E; Zarco, N; Vergara, P; Shibayama, M; Segovia, J; Tsutsumi, V; Muriel, P

    2016-02-01

    Here we evaluated the ability of L-theanine in preventing experimental hepatic cirrhosis and investigated the roles of nuclear factor-κB (NF-κB) activation as well as transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) regulation. Experimental hepatic cirrhosis was established by the administration of carbon tetrachloride (CCl4) to rats (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks), and at the same time, adding L-theanine (8.0 mg/kg) to the drinking water. Rats had ad libitum access to water and food throughout the treatment period. CCl4 treatment promoted NF-κB activation and increased the expression of both TGF-β and CTGF. CCl4 increased the serum activities of alanine aminotransferase and γ-glutamyl transpeptidase and the degree of lipid peroxidation, and it also induced a decrease in the glutathione and glutathione disulfide ratio. L-Theanine prevented increased expression of NF-κB and down-regulated the pro-inflammatory (interleukin (IL)-1β and IL-6) and profibrotic (TGF-β and CTGF) cytokines. Furthermore, the levels of messenger RNA encoding these proteins decreased in agreement with the expression levels. L-Theanine promoted the expression of the anti-inflammatory cytokine IL-10 and the fibrolytic enzyme metalloproteinase-13. Liver hydroxyproline contents and histopathological analysis demonstrated the anti-fibrotic effect of l-theanine. In conclusion, L-theanine prevents CCl4-induced experimental hepatic cirrhosis in rats by blocking the main pro-inflammatory and pro-fibrogenic signals.

  17. Connective Tissue Growth Factor in Regulation of RhoA Mediated Cytoskeletal Tension Associated Osteogenesis of Mouse Adipose-Derived Stromal Cells

    PubMed Central

    Xu, Yue; Wagner, Diane R.; Bekerman, Elena; Chiou, Michael; James, Aaron W.; Carter, Dennis; Longaker, Michael T.

    2010-01-01

    Background Cytoskeletal tension is an intracellular mechanism through which cells convert a mechanical signal into a biochemical response, including production of cytokines and activation of various signaling pathways. Methods/Principal Findings Adipose-derived stromal cells (ASCs) were allowed to spread into large cells by seeding them at a low-density (1,250 cells/cm2), which was observed to induce osteogenesis. Conversely, ASCs seeded at a high-density (25,000 cells/cm2) featured small cells that promoted adipogenesis. RhoA and actin filaments were altered by changes in cell size. Blocking actin polymerization by Cytochalasin D influenced cytoskeletal tension and differentiation of ASCs. To understand the potential regulatory mechanisms leading to actin cytoskeletal tension, cDNA microarray was performed on large and small ASCs. Connective tissue growth factor (CTGF) was identified as a major regulator of osteogenesis associated with RhoA mediated cytoskeletal tension. Subsequently, knock-down of CTGF by siRNA in ASCs inhibited this osteogenesis. Conclusions/Significance We conclude that CTGF is important in the regulation of cytoskeletal tension mediated ASC osteogenic differentiation. PMID:20585662

  18. Mechanisms of bradykinin-induced expression of connective tissue growth factor and nephrin in podocytes.

    PubMed

    Abou Msallem, J; Chalhoub, H; Al-Hariri, M; Saad, L; Jaffa, M A; Ziyadeh, F N; Jaffa, A A

    2015-12-01

    Diabetic nephropathy (DN) is the main cause of morbidity and mortality in diabetes and is characterized by mesangial matrix deposition and podocytopathy, including podocyte loss. The risk factors and mechanisms involved in the pathogenesis of DN are still not completely defined. In the present study, we aimed to understand the cellular mechanisms through which activation of B2 kinin receptors contribute to the initiation and progression of DN. Stimulation of cultured rat podocytes with bradykinin (BK) resulted in a significant increase in ROS generation, and this was associated with a significant increase in NADPH oxidase (NOX)1 and NOX4 protein and mRNA levels. BK stimulation also resulted in a signicant increase in the phosphorylation of ERK1/2 and Akt, and this effect was inhibited in the presence of NOX1 and Nox4 small interfering (si)RNA. Furthermore, podocytes stimulated with BK resulted in a significant increase in protein and mRNA levels of connective tissue growth factor (CTGF) and, at the same time, a significant decrease in protein and mRNA levels of nephrin. siRNA targeted against NOX1 and NOX4 significantly inhibited the BK-induced increase in CTGF. Nephrin expression was increased in response to BK in the presence of NOX1 and NOX4 siRNA, thus implicating a role for NOXs in modulating the BK response in podocytes. Moreover, nephrin expression in response to BK was also significantly increased in the presence of siRNA targeted against CTGF. These findings provide novel aspects of BK signal transduction pathways in pathogenesis of DN and identify novel targets for interventional strategies.

  19. Growth factors and cytokines in wound healing.

    PubMed

    Barrientos, Stephan; Stojadinovic, Olivera; Golinko, Michael S; Brem, Harold; Tomic-Canic, Marjana

    2008-01-01

    Wound healing is an evolutionarily conserved, complex, multicellular process that, in skin, aims at barrier restoration. This process involves the coordinated efforts of several cell types including keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets. The migration, infiltration, proliferation, and differentiation of these cells will culminate in an inflammatory response, the formation of new tissue and ultimately wound closure. This complex process is executed and regulated by an equally complex signaling network involving numerous growth factors, cytokines and chemokines. Of particular importance is the epidermal growth factor (EGF) family, transforming growth factor beta (TGF-beta) family, fibroblast growth factor (FGF) family, vascular endothelial growth factor (VEGF), granulocyte macrophage colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), interleukin (IL) family, and tumor necrosis factor-alpha family. Currently, patients are treated by three growth factors: PDGF-BB, bFGF, and GM-CSF. Only PDGF-BB has successfully completed randomized clinical trials in the Unites States. With gene therapy now in clinical trial and the discovery of biodegradable polymers, fibrin mesh, and human collagen serving as potential delivery systems other growth factors may soon be available to patients. This review will focus on the specific roles of these growth factors and cytokines during the wound healing process.

  20. Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration.

    PubMed

    Mori, Ryoichi; Kondo, Toshikazu; Ohshima, Tohru; Ishida, Yuko; Mukaida, Naofumi

    2002-07-01

    To clarify biological roles of tumor necrosis factor receptor p55 (TNF-Rp55) -mediated signals in wound healing, skin excisions were prepared in BALB/c (WT) and TNF-Rp55-deficient (KO) mice. In WT mice, the wound area was reduced to 50% of the original area 6 days after injury, with angiogenesis and collagen accumulation. Histopathologically, reepithelialization rate was approximately 80% 6 days. Myeloperoxidase activity and macrophage recruitment were the most evident 1 and 6 days after injury, respectively. Gene expression of adhesion molecules, interleukin 1alpha (IL-1alpha), IL-1beta, monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-2, transforming growth factor beta1 (TGF-beta1) connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), Flt-1, and Flk-1 was enhanced at the wound site. In KO mice, an enhancement in angiogenesis, collagen content, and reepithelialization was accelerated with the increased gene expression of TGF-beta1, CTGF, VEGF, Flt-1, and Flk-1 at the wound sites, resulting in accelerated wound healing compared with WT mice. In contrast, leukocyte infiltration, mRNA expression of adhesion molecules, and cytokines were significantly reduced in KO mice. These observations suggest that TNF-Rp55-mediated signals have some role in promoting leukocyte infiltration at the wound site and negatively affect wound healing, probably by reducing angiogenesis and collagen accumulation.

  1. Actions of activin A, connective tissue growth factor, hepatocyte growth factor and teratocarcinoma-derived growth factor 1 on the development of the bovine preimplantation embryo.

    PubMed

    Kannampuzha-Francis, Jasmine; Tribulo, Paula; Hansen, Peter J

    2016-05-17

    The reproductive tract secretes bioactive molecules collectively known as embryokines that can regulate embryonic growth and development. In the present study we tested four growth factors expressed in the endometrium for their ability to modify the development of the bovine embryo to the blastocyst stage and alter the expression of genes found to be upregulated (bone morphogenetic protein 15 (BMP15) and keratin 8, type II (KRT8)) or downregulated (NADH dehydrogenase 1 (ND1) and S100 calcium binding protein A10 (S100A10)) in embryos competent to develop to term. Zygotes were treated at Day 5 with 0.01, 0.1 or 1.0 nM growth factor. The highest concentration of activin A increased the percentage of putative zygotes that developed to the blastocyst stage. Connective tissue growth factor (CTGF) increased the number of cells in the inner cell mass (ICM), decreased the trophectoderm : ICM ratio and increased blastocyst expression of KRT8 and ND1. The lowest concentration of hepatocyte growth factor (HGF) reduced the percentage of putative zygotes becoming blastocysts. Teratocarcinoma-derived growth factor 1 increased total cell number at 0.01 nM and expression of S100A10 at 1.0 nM, but otherwise had no effects. Results confirm the prodevelopmental actions of activin A and indicate that CTGF may also function as an embryokine by regulating the number of ICM cells in the blastocyst and altering gene expression. Low concentrations of HGF were inhibitory to development.

  2. Paraquat increases connective tissue growth factor expression and impairs lung fibroblast proliferation and viscoelasticity.

    PubMed

    Zhang, N; Xie, Y-P; Pang, L; Zang, X-X; Wang, J; Shi, D; Wu, Y; Liu, X-L; Wang, G-H

    2014-12-01

    This in vitro study was designed to investigate the molecular mechanisms of paraquat-induced damage using cultured human fetal lung fibroblasts (MRC-5 cells), in order to promote the development of improved therapies for paraquat poisoning. Paraquat's effects on proliferation were examined by flow cytometry, on viscoelasticity by the micropipette aspiration technique, and on connective tissue growth factor (CTGF) expression by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Paraquat was found to significantly reduce the proliferation index of MRC-5 cells in a concentration-dependent manner (p < 0.05) and to significantly impair the viscoelastic properties in a time-independent manner (p < 0.05). Exposure to paraquat led to a significant and time-dependent increase in CTGF expression (p < 0.05) and induced changes in the morphology and biomechanical characteristics of the MRC-5 cells. These findings not only provide novel insights into the mechanisms of paraquat-induced lung fibrosis but may represent useful targets of improved molecular-based therapies for paraquat poisoning.

  3. Chimeric DNA-RNA hammerhead ribozyme targeting transforming growth factor-beta 1 mRNA inhibits neointima formation in rat carotid artery after balloon injury.

    PubMed

    Ando, Hideyuki; Fukuda, Noboru; Kotani, Motoko; Yokoyama, Shin ichiro; Kunimoto, Satoshi; Matsumoto, Koichi; Saito, Satoshi; Kanmatsuse, Katsuo; Mugishima, Hideo

    2004-01-12

    We designed and synthesized a chimeric DNA-RNA hammerhead ribozyme targeting transforming growth factor (TGF)-beta 1 mRNA and found that this ribozyme effectively and specifically inhibited growth of vascular smooth muscle cells. We examined the effects of the chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta 1 mRNA on neointima formation and investigated the underlying mechanism to develop a possible gene therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty. Expression of mRNAs encoding TGF-beta 1, p27kip1, and connective tissue growth factor (CTGF) in carotid artery increased after balloon injury. Fluorescein-isothiocyanate (FITC)-labeled ribozyme was taken up into the midlayer smooth muscle of the injured carotid artery. Both 2 and 5 mg of ribozyme reduced neointima formation by 65% compared to that of controls. Ribozyme markedly decreased expression of TGF-beta 1 mRNA and protein in injured vessel. Mismatch ribozyme had no effect on expression of TGF-beta 1 mRNA protein in injured vessel. Ribozyme markedly decreased expression of fibronectin, p27kip1, and CTGF mRNAs in injured vessel, whereas a mismatch ribozyme had no effect on these mRNAs. These findings indicate that the chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta 1 mRNA inhibits neointima formation in rat carotid artery after balloon injury with suppression of TGF-beta 1 and inhibition of extracellular matrix and CTGF. In conclusion, the hammerhead ribozyme against TGF-beta 1 may have promise as a therapy for coronary artery restenosis after percutaneous transluminal coronary angioplasty.

  4. TNF-alpha, but not IFN-gamma, regulates CCN2 (CTGF), collagen type I, and proliferation in mesangial cells: possible roles in the progression of renal fibrosis.

    PubMed

    Cooker, Laurinda A; Peterson, Darryl; Rambow, Joann; Riser, Melisa L; Riser, Rebecca E; Najmabadi, Feridoon; Brigstock, David; Riser, Bruce L

    2007-07-01

    Connective tissue growth factor (CCN2) is a profibrotic factor acting downstream and independently of TGF-beta to mediate renal fibrosis. Although inflammation is often involved in the initiation and/or progression of fibrosis, the role of inflammatory cytokines in regulation of glomerular CCN2 expression, cellular proliferation, and extracellular matrix accumulation is unknown. We studied two such cytokines, TNF-alpha and IFN-gamma, for their effects on cultured mesangial cells in the presence or absence of TGF-beta, as a model for progressive renal fibrosis. Short-term treatment with TNF-alpha, like TGF-beta, significantly increased secreted CCN2 per cell, but unlike TGF-beta inhibited cellular replication. TNF-alpha combined with TGF-beta further increased CCN2 secretion and mRNA levels and reduced proliferation. Surprisingly, however, TNF-alpha treatment decreased baseline collagen type I protein and mRNA levels and largely blocked their stimulation by TGF-beta. Long-term treatment with TGF-beta or TNF-alpha alone no longer increased CCN2 protein levels. However, the combination synergistically increased CCN2. IFN-gamma had no effect on either CCN2 or collagen activity and produced a mild inhibition of TGF-beta-induced collagen only at a high concentration (500 U/ml). In summary, we report a strong positive regulatory role for TNF-alpha, but not IFN-gamma, in CCN2 production and secretion, including that driven by TGF-beta. The stimulation of CCN2 release by TNF-alpha, unlike TGF-beta, is independent of cellular proliferation and not linked to increased collagen type I accumulation. This suggests that the paradigm of TGF-beta-driven CCN2 with subsequent collagen production may be overridden by an as yet undefined inhibitory mechanism acting either directly or indirectly on matrix metabolism.

  5. Dynamic Analysis of the Expression of the TGFβ/SMAD2 Pathway and CCN2/CTGF during Early Steps of Tooth Development

    PubMed Central

    Pacheco, Marcos S.; Reis, Alice H.; Aguiar, Diego P.; Lyons, Karen M.; Abreu, José G.

    2009-01-01

    Background/Aims CCN2 is present during tooth development. However, the relationship between CCN2 and the transforming growth factor β (TGFβ)/SMAD2/3 signaling cascade during early stages of tooth development is unclear. Here, we compare the expression of CCN2 and TGFβ/SMAD2/3 components during tooth development, and analyze the functioning of TGFβ/SMAD2/3 in wild-type (WT) and Ccn2 null (Ccn2−/−) mice. Methods Coronal sections of mice on embryonic day (E)11.5, E12.5, E13.5, E14.5 and E18.5 from WT and Ccn2−/− were immunoreacted to detect CCN2 and components of the TGFβ signaling pathway and assayed for 5′-bromo-2′-deoxyuridine immunolabeling and proliferating cell nuclear antigen immunostaining. Results CCN2 and TGFβ signaling components such as TGFβ1, TGFβ receptor II, SMADs2/3 and SMAD4 were expressed in inducer tissues during early stages of tooth development. Proliferation analysis in these areas showed that epithelial cells proliferate less than mesenchymal cells from E11.5 to E13.5, while at E14.5 they proliferate more than mesenchymal cells. We did not find a correlation between functioning of the TGFβ1 cascade and CCN2 expression because Ccn2−/− mice showed neither a reduction in SMAD2 phosphorylation nor a difference in cell proliferation. Conclusion CCN2 and the TGFβ/SMAD2/3 signaling pathway are active in signaling centers of tooth development where proliferation is dynamic, but these mechanisms may act independently. PMID:18089935

  6. Expression of cyclooxygenase-1 and cyclooxygenase-2, syndecan-1 and connective tissue growth factor in benign and malignant breast tissue from premenopausal women.

    PubMed

    Fahlén, M; Zhang, H; Löfgren, L; Masironi, B; von Schoultz, E; von Schoultz, B; Sahlin, L

    2017-02-21

    Stromal factors have been identified as important for tumorigenesis and metastases of breast cancer. From 49 premenopausal women, samples were collected from benign or malignant tumors and the seemingly normal tissue adjacent to the tumor. The factors studied, with real-time polymerase chain reaction (PCR) and immunohistochemistry, were cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), syndecan-1 (S-1) and connective tissue growth factor (CTGF). COX-1 and S-1 mRNA levels were higher in the malignant tumors than in normal and benign tissues. The COX-2 mRNA level was lower in the malignant tumor than in the normal tissue, while CTGF mRNA did not differ between the groups. COX-1 immunostaining was higher in stroma from malignant tumors than in benign tissues, whereas COX-2 immunostaining was higher in the malignant tissue. Glandular S-1 immunostaining was lower in malignant tumors compared to benign and normal tissues, and the opposite was found in stroma. Conclusively, mRNA levels of COX-1 and COX-2 were oppositely regulated, with COX-1 being increased in the malignant tumor while COX-2 was decreased. S-1 protein localization switched from glandular to stromal cells in malignant tissues. Thus, these markers are, in premenopausal women, localized and regulated differently in normal/benign breast tissue as compared to the malignant tumor.

  7. Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis.

    PubMed

    Dean, Richard A; Butler, Georgina S; Hamma-Kourbali, Yamina; Delbé, Jean; Brigstock, David R; Courty, José; Overall, Christopher M

    2007-12-01

    Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic functions by the release of cytokines or proteolytically generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2-/- mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope-coded affinity tag labeling of proteins analyzed by multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2-/- cells and those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein 6, follistatin-like 1, and cystatin C protein cleavage by MMP-2 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis.

  8. Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis.

    PubMed

    Cheung, Laurence C; Strickland, Deborah H; Howlett, Meegan; Ford, Jette; Charles, Adrian K; Lyons, Karen M; Brigstock, David R; Goldschmeding, Roel; Cole, Catherine H; Alexander, Warren S; Kees, Ursula R

    2014-07-01

    Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis.

  9. Molecular factors involved in the hypolipidemic- and insulin-sensitizing effects of a ginger (Zingiber officinale Roscoe) extract in rats fed a high-fat diet.

    PubMed

    de Las Heras, Natalia; Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; López-Farré, Antonio; Ruiz-Roso, Baltasar; Lahera, Vicente

    2017-02-01

    Hypolipidemic and hypoglycemic properties of ginger in animal models have been reported. However, information related to the mechanisms and factors involved in the metabolic effects of ginger at a hepatic level are limited. The aim of the present study was to investigate molecular factors involved in the hypoglycemic and hypolipidemic effects of a hydroethanolic ginger extract (GE) in the liver of rats fed a high-fat diet (HFD). The study was conducted in male Wistar rats divided into the following 3 groups: (i) Rats fed a standard diet (3.5% fat), the control group; (ii) rats fed an HFD (33.5% fat); and (iii) rats fed an HFD treated with GE (250 mg·kg(-1)·day(-1)) for 5 weeks (HFD+GE). Plasma levels of glucose, insulin, lipid profile, leptin, and adiponectin were measured. Liver expression of glycerol phosphate acyltransferase (GPAT), cholesterol 7 alpha-hydroxylase, peroxisome proliferator-activated receptors (PPAR), PPARα and PPARγ, glucose transporter 2 (GLUT-2), liver X receptor, sterol regulatory element-binding protein (SREBP1c), connective tissue growth factor (CTGF), and collagen I was measured. Data were analyzed using a 1-way ANOVA, followed by a Newman-Keuls test if differences were noted. The study showed that GE improved lipid profile and attenuated the increase of plasma levels of glucose, insulin, and leptin in HFD rats. This effect was associated with a higher liver expression of PPARα, PPARγ, and GLUT-2 and an enhancement of plasma adiponectin levels. Furthermore, GE reduced liver expression of GPAT, SREBP1c, CTGF, and collagen I. The results suggest that GE might be considered as an alternative therapeutic strategy in the management of overweight and hepatic and metabolic-related alterations.

  10. Velvet antler peptide prevents pressure overload-induced cardiac fibrosis via transforming growth factor (TGF)-β1 pathway inhibition.

    PubMed

    Zhao, Lihong; Mi, Yang; Guan, Hongya; Xu, Yan; Mei, Yingwu

    2016-07-15

    Velvet antlers (VAs) are commonly used in traditional Chinese medicine and invigorant and contain many functional components for health promotion. The velvet antler peptide sVAP32 is one of active components in VAs; based on structural study, the sVAP32 interacts with TGF-β1 receptors and disrupts the TGF-β1 pathway. We hypothesized that sVAP32 prevents cardiac fibrosis from pressure overload by blocking TGF-β1 signaling. Sprague-Dawley rats underwent transverse aortic constriction (TAC) or a sham operation. After one month, rats received either sVAP32 (15mg/kg/day) or vehicle for an additional one month. TAC surgery induced significant cardiac dysfunction, fibroblast activation and fibrosis; these effects were improved by treatment with sVAP32. In the heart tissue, TAC remarkably increased the expression of TGF-β1 and connective tissue growth factor (CTGF), reactive oxygen species levels, and the phosphorylation levels of Smad2/3 and extracellular signal-regulated kinases 1/2 (ERK1/2). SVAP32 inhibited the increases in reactive oxygen species levels, CTGF expression and the phosphorylation of Smad2/3 and ERK1/2, but not TGF-β1 expression. In cultured cardiac fibroblasts, angiotensin II (Ang II) had similar effects compared to TAC surgery, such as increases in α-SMA-positive cardiac fibroblasts and collagen synthesis. SVAP32 eliminated these effects by disrupting TGF-β1 binding to its receptors and blocking Ang II/TGF-β1 downstream signaling. These results demonstrated that sVAP32 has anti-fibrotic effects by blocking the TGF-β1 pathway in cardiac fibroblasts.

  11. A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis

    PubMed Central

    Shiwen, Xu; Stratton, Richard; Nikitorowicz-Buniak, Joanna; Ahmed-Abdi, Bahja; Ponticos, Markella; Denton, Christopher; Abraham, David; Takahashi, Ayuko; Suki, Bela; Layne, Matthew D.; Lafyatis, Robert; Smith, Barbara D.

    2015-01-01

    In scleroderma (systemic sclerosis, SSc), persistent activation of myofibroblast leads to severe skin and organ fibrosis resistant to therapy. Increased mechanical stiffness in the involved fibrotic tissues is a hallmark clinical feature and a cause of disabling symptoms. Myocardin Related Transcription Factor-A (MRTF-A) is a transcriptional co-activator that is sequestered in the cytoplasm and translocates to the nucleus under mechanical stress or growth factor stimulation. Our objective was to determine if MRTF-A is activated in the disease microenvironment to produce more extracellular matrix in progressive SSc. Immunohistochemistry studies demonstrate that nuclear translocation of MRTF-A in scleroderma tissues occurs in keratinocytes, endothelial cells, infiltrating inflammatory cells, and dermal fibroblasts, consistent with enhanced signaling in multiple cell lineages exposed to the stiff extracellular matrix. Inhibition of MRTF-A nuclear translocation or knockdown of MRTF-A synthesis abolishes the SSc myofibroblast enhanced basal contractility and synthesis of type I collagen and inhibits the matricellular profibrotic protein, connective tissue growth factor (CCN2/CTGF). In MRTF-A null mice, basal skin and lung stiffness was abnormally reduced and associated with altered fibrillar collagen. MRTF-A has a role in SSc fibrosis acting as a central regulator linking mechanical cues to adverse remodeling of the extracellular matrix. PMID:25955164

  12. Expression of extracellular matrix components and related growth factors in human tendon and muscle after acute exercise.

    PubMed

    Heinemeier, K M; Bjerrum, S S; Schjerling, P; Kjaer, M

    2013-06-01

    Acute kicking exercise induces collagen synthesis in both tendon and muscle in humans, but it is not known if this relates to increased collagen transcription and if other matrix genes are regulated. Young men performed 1 h of one-leg kicking at 67% of max workload. Biopsies were taken from the patellar tendon and vastus lateralis muscle of each leg at 2 (n = 10), 6 (n = 11), or 26 h (n = 10) after exercise. Levels of messenger ribonucleic acid mRNA for collagens, noncollagenous matrix proteins, and growth factors were measured with real-time reverse transcription polymerase chain reaction. In tendon, gene expression was unchanged except for a decrease in insulin-like growth factor-IEa (IGF-IEa; P < 0.05). In muscle, collagen expression was not significantly altered, while levels of connective tissue growth factor (CTGF), IGF-IEa, transforming growth factor-β1, -2 (TGF-β), and the TGF-β receptor II mRNA were increased (P < 0.05). Matrix components tenascin-C, fibronectin, and decorin were also induced in loaded muscle (P < 0.05), while fibromodulin was unaffected. In conclusion, the relatively robust changes in matrix components and related growth factors in muscle indicate a stimulation of extracellular matrix even with moderate exercise. However, in tendon tissue, this exercise model does not appear to induce any anabolic response on the transcriptional level.

  13. HTLV-1 bZIP factor enhances TGF-β signaling through p300 coactivator.

    PubMed

    Zhao, Tiejun; Satou, Yorifumi; Sugata, Kenji; Miyazato, Paola; Green, Patrick L; Imamura, Takeshi; Matsuoka, Masao

    2011-08-18

    Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-β (TGF-β)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-β signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-β response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-β. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-β signaling. Our results suggest that HBZ, by enhancing TGF-β signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence.

  14. Angiotensin II-induced pro-fibrotic effects require p38MAPK activity and transforming growth factor beta 1 expression in skeletal muscle cells.

    PubMed

    Morales, María Gabriela; Vazquez, Yaneisi; Acuña, María José; Rivera, Juan Carlos; Simon, Felipe; Salas, José Diego; Alvarez Ruf, Joel; Brandan, Enrique; Cabello-Verrugio, Claudio

    2012-11-01

    Fibrotic disorders are typically characterised by excessive connective tissue and extracellular matrix (ECM) deposition that preclude the normal healing of different tissues. Several skeletal muscle dystrophies are characterised by extensive fibrosis. Among the factors involved in skeletal muscle fibrosis is angiotensin II (Ang-II), a key protein of the renin-angiotensin system (RAS). We previously demonstrated that myoblasts responded to Ang-II by increasing the ECM protein levels mediated by AT-1 receptors, implicating an Ang-II-induced reactive oxygen species (ROS) by a NAD(P)H oxidase-dependent mechanism. In this paper, we show that in myoblasts, Ang-II induced the increase of transforming growth factor beta 1 (TGF-β1) and connective tissue growth factor (CTGF) expression through its AT-1 receptor. This effect is dependent of the NAD(P)H oxidase (NOX)-induced ROS, as indicated by a decrease of the expression of both pro-fibrotic factors when the ROS production was inhibited via the NOX inhibitor apocynin. The increase in pro-fibrotic factors levels was paralleled by enhanced p38MAPK and ERK1/2 phosphorylation in response to Ang-II. However, only the p38MAPK activity was critical for the Ang-II-induced fibrotic effects, as indicated by the decrease in the Ang-II-induced TGF-β1 and CTGF expression and fibronectin levels by SB-203580, an inhibitor of the p38MAPK, but not by U0126, an inhibitor of ERK1/2 phosphorylation. Furthermore, we showed that the Ang-II-dependent p38MAPK activation, but not the ERK1/2 phosphorylation, was necessary for the NOX-derived ROS. In addition, we demonstrated that TGF-β1 expression was required for the Ang-II-induced pro-fibrotic effects evaluated by using SB-431542, an inhibitor of TGF-βRI kinase activity, and by knocking down TGF-β1 levels by shRNA technique. These results strongly suggest that the fibrotic response to Ang-II is mediated by the AT-1 receptor and requires the p38MAPK phosphorylation, NOX-induced ROS, and TGF

  15. Role of CTGF in White Matter Development in Tuberous Sclerosis

    DTIC Science & Technology

    2014-02-01

    Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...the oligodendrocytes by PLP promoter driven GFP expression. In addition to this finding , we now demonstrate the decrease in mature oligodendrocyte...TSC1/2 function and oligodendrocyte maturation, thus myelination. While much of the pathology of TSC is established during embryonic development

  16. CCN2/Connective Tissue Growth Factor Is Essential for Pericyte Adhesion and Endothelial Basement Membrane Formation during Angiogenesis

    PubMed Central

    Huang, Bau-Lin; van Handel, Ben; Hofmann, Jennifer J.; Chen, Tom T.; Choi, Aaron; Ong, Jessica R.; Benya, Paul D.; Mikkola, Hanna; Iruela-Arispe, M. Luisa; Lyons, Karen M.

    2012-01-01

    CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes. PMID:22363445

  17. CCN2 (Connective Tissue Growth Factor) is essential for extracellular matrix production and integrin signaling in chondrocytes

    PubMed Central

    Nishida, Takashi; Kawaki, Harumi; Baxter, Ruth M.; DeYoung, R. Andrea; Takigawa, Masaharu

    2007-01-01

    The matricellular protein CCN2 (Connective Tissue Growth Factor; CTGF) is an essential mediator of ECM composition, as revealed through analysis of Ccn2 deficient mice. These die at birth due to complications arising from impaired endochondral ossification. However, the mechanism(s) by which CCN2 mediates its effects in cartilage are unclear. We investigated these mechanisms using Ccn2−/− chondrocytes. Expression of type II collagen and aggrecan were decreased in Ccn2−/− chondrocytes, confirming a defect in ECM production. Ccn2−/− chondrocytes also exhibited impaired DNA synthesis and reduced adhesion to fibronectin. This latter defect is associated with decreased expression of α5 integrin. Moreover, CCN2 can bind to integrin α5β1 in chondrocytes and can stimulate increased expression of integrin α5. Consistent with an essential role for CCN2 as a ligand for integrins, immunofluorescence and Western blot analysis revealed that levels of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK)1/2 phosphorylation were reduced in Ccn2−/− chondrocytes. These findings argue that CCN2 exerts major effects in chondrocytes through its ability to (1) regulate ECM production and integrin α5 expression, (2) engage integrins and (3) activate integrin-mediated signaling pathways. PMID:18481209

  18. Dinitrophenol modulates gene expression levels of angiogenic, cell survival and cardiomyogenic factors in bone marrow derived mesenchymal stem cells.

    PubMed

    Ali, Anwar; Akhter, Muhammad Aleem; Haneef, Kanwal; Khan, Irfan; Naeem, Nadia; Habib, Rakhshinda; Kabir, Nurul; Salim, Asmat

    2015-01-25

    Various preconditioning strategies influence regeneration properties of stem cells. Preconditioned stem cells generally show better cell survival, increased differentiation, enhanced paracrine effects, and improved homing to the injury site by regulating the expression of tissue-protective cytokines and growth factors. In this study, we analyzed gene expression pattern of growth factors through RT-PCR after treatment of mesenchymal stem cells (MSCs) with a metabolic inhibitor, 2,4 dinitrophenol (DNP) and subsequent re-oxygenation for periods of 2, 6, 12 and 24h. These growth factors play important roles in cardiomyogenesis, angiogenesis and cell survival. Mixed pattern of gene expression was observed depending on the period of re-oxygenation. Of the 13 genes analyzed, ankyrin repeat domain 1 (Ankrd1) and GATA6 were downregulated after DNP treatment and subsequent re-oxygenations. Ankrd1 expression was, however, increased after 24h of re-oxygenation. Placental growth factor (Pgf), endoglin (Eng), neuropilin (Nrp1) and jagged 1 (Jag1) were up-regulated after DNP treatment. Gradual increase was observed as re-oxygenation advances and by the end of the re-oxygenation period the expression started to decrease and ultimately regained normal values. Epiregulin (Ereg) was not expressed in normal MSCs but its expression increased gradually from 2 to 24h after re-oxygenation. No change was observed in the expression level of connective tissue growth factor (Ctgf) at any time period after re-oxygenation. Kindlin3, kinase insert domain receptor (Kdr), myogenin (Myog), Tbx20 and endothelial tyrosine kinase (Tek) were not expressed either in normal cells or cells treated with DNP. It can be concluded from the present study that MSCs adjust their gene expression levels under the influence of DNP induced metabolic stress. Their levels of expression vary with varying re-oxygenation periods. Preconditioning of MSCs with DNP can be used for enhancing the potential of these cells for

  19. Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

    PubMed

    Imai, Rika; Asai, Kanae; Hanai, Jun-ichi; Takenaka, Masaru

    2015-07-01

    Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

  20. Parasite-Derived Neurotrophic Factor/trans-Sialidase of Trypanosoma cruzi Links Neurotrophic Signaling to Cardiac Innate Immune Response

    PubMed Central

    Salvador, Ryan; Aridgides, Daniel

    2014-01-01

    The Chagas' disease parasite Trypanosoma cruzi elicits a potent inflammatory response in acutely infected hearts that keeps parasitism in check and triggers cardiac abnormalities. A most-studied mechanism underlying innate immunity in T. cruzi infection is Toll-like receptor (TLR) activation by lipids and other parasite molecules. However, yet-to-be-identified pathways should exist. Here, we show that T. cruzi strongly upregulates monocyte chemoattractant protein 1 (MCP-1)/CCL2 and fractalkine (FKN)/CX3CL1 in cellular and mouse models of heart infection. Mechanistically, upregulation of MCP-1 and FKN stems from the interaction of parasite-derived neurotrophic factor (PDNF)/trans-sialidase with neurotrophic receptors TrkA and TrkC, as assessed by pharmacological inhibition, neutralizing antibodies, and gene silencing studies. Administration of a single dose of intravenous PDNF to naive mice results in a dose-dependent increase in MCP-1 and FKN in the heart and liver with pulse-like kinetics that peak at 3 h postinjection. Intravenous PDNF also augments MCP-1 and FKN in TLR signaling-deficient MyD88-knockout mice, underscoring the MyD88-independent action of PDNF. Although single PDNF injections do not increase MCP-1 and FKN receptors, multiple PDNF injections at short intervals up the levels of receptor transcripts in the heart and liver, suggesting that sustained PDNF triggers cell recruitment at infection sites. Thus, given that MCP-1 and FKN are chemokines essential to the recruitment of immune cells to combat inflammation triggers and to enhance tissue repair, our findings uncover a new mechanism in innate immunity against T. cruzi infection mediated by Trk signaling akin to an endogenous inflammatory and fibrotic pathway resulting from cardiomyocyte-TrkA recognition by matricellular connective tissue growth factor (CTGF/CCN2). PMID:24935974

  1. Novel factors in the pathogenesis of psoriasis and potential drug candidates are found with systems biology approach.

    PubMed

    Manczinger, Máté; Kemény, Lajos

    2013-01-01

    Psoriasis is a multifactorial inflammatory skin disease characterized by increased proliferation of keratinocytes, activation of immune cells and susceptibility to metabolic syndrome. Systems biology approach makes it possible to reveal novel important factors in the pathogenesis of the disease. Protein-protein, protein-DNA, merged (containing both protein-protein and protein-DNA interactions) and chemical-protein interaction networks were constructed consisting of differentially expressed genes (DEG) between lesional and non-lesional skin samples of psoriatic patients and/or the encoded proteins. DEGs were determined by microarray meta-analysis using MetaOMICS package. We used STRING for protein-protein, CisRED for protein-DNA and STITCH for chemical-protein interaction network construction. General network-, cluster- and motif-analysis were carried out in each network. Many DEG-coded proteins (CCNA2, FYN, PIK3R1, CTGF, F3) and transcription factors (AR, TFDP1, MEF2A, MECOM) were identified as central nodes, suggesting their potential role in psoriasis pathogenesis. CCNA2, TFDP1 and MECOM might play role in the hyperproliferation of keratinocytes, whereas FYN may be involved in the disturbed immunity in psoriasis. AR can be an important link between inflammation and insulin resistance, while MEF2A has role in insulin signaling. A controller sub-network was constructed from interlinked positive feedback loops that with the capability to maintain psoriatic lesional phenotype. Analysis of chemical-protein interaction networks detected 34 drugs with previously confirmed disease-modifying effects, 23 drugs with some experimental evidences, and 21 drugs with case reports suggesting their positive or negative effects. In addition, 99 unpublished drug candidates were also found, that might serve future treatments for psoriasis.

  2. HMG-CoA reductase inhibitors decrease angiotensin II-induced vascular fibrosis: role of RhoA/ROCK and MAPK pathways.

    PubMed

    Rupérez, Mónica; Rodrigues-Díez, Raquel; Blanco-Colio, Luis Miguel; Sánchez-López, Elsa; Rodríguez-Vita, Juan; Esteban, Vanesa; Carvajal, Gisselle; Plaza, Juan José; Egido, Jesús; Ruiz-Ortega, Marta

    2007-08-01

    3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) present beneficial effects in cardiovascular diseases. Angiotensin II (Ang II) contributes to cardiovascular damage through the production of profibrotic factors, such as connective tissue growth factor (CTGF). Our aim was to investigate whether HMG-CoA reductase inhibitors could modulate Ang II responses, evaluating CTGF expression and the mechanisms underlying this process. In cultured vascular smooth muscle cells (VSMCs) atorvastatin and simvastatin inhibited Ang II-induced CTGF production. The inhibitory effect of statins on CTGF upregulation was reversed by mevalonate and geranylgeranylpyrophosphate, suggesting that RhoA inhibition could be involved in this process. In VSMCs, statins inhibited Ang II-induced Rho membrane localization and activation. In these cells Ang II regulated CTGF via RhoA/Rho kinase activation, as shown by inhibition of Rho with C3 exoenzyme, RhoA dominant-negative overexpression, and Rho kinase inhibition. Furthermore, activation of p38MAPK and JNK, and redox process were also involved in Ang II-mediated CTGF upregulation, and were downregulated by statins. In rats infused with Ang II (100 ng/kg per minute) for 2 weeks, treatment with atorvastatin (5 mg/kg per day) diminished aortic CTGF and Rho activation without blood pressure modification. Rho kinase inhibition decreased CTGF upregulation in rat aorta, mimicking statin effect. CTGF is a vascular fibrosis mediator. Statins diminished extracellular matrix (ECM) overexpression caused by Ang II in vivo and in vitro. In summary, HMG-CoA reductase inhibitors inhibit several intracellular signaling systems activated by Ang II (RhoA/Rho kinase and MAPK pathways and redox process) involved in the regulation of CTGF. Our results may explain, at least in part, some beneficial effects of statins in cardiovascular diseases.

  3. Hypoxia-Inducible Factor-1alpha and MAPK Co-Regulate Activation of Hepatic Stellate Cells upon Hypoxia Stimulation

    PubMed Central

    Guan, Fei; Xiao, Yan; Deng, Jing; Chen, Huoying; Chen, Xiaolin; Li, Jianrong; Huang, Hanju; Shi, Chunwei

    2013-01-01

    Background Hepatic stellate cell (HSC) plays a key role in pathogenesis of liver fibrosis. During liver injury, hypoxia in local micro-environment is inevitable. Hif-1α is the key transcriptional regulation factor that induces cell’s adaptive responses to hypoxia. Recently, it was reported that MAPK is involved in regulation of Hif-1α activity. Aims To explore whether Hif-1α regulates HSC activation upon hypoxia, and whether MAPK affects Hif-1α-regulated signaling cascades, thus providing new targets for preventing liver fibrosis. Methods Hif-1α expression in livers of Schistosomajaponicum infected BALB/c mice was detected with western blot and immunohistochemistry. A rat cell line of HSC, HSC-T6, was cultured in 1% oxygen. HSC activation, including F-actin reorganization, increase of vimentin and α-SMA, was detected with western blot or immunocytochemistry. Cells were transfected with specific siRNA to Hif-1α, expression of activation markers, transcription of fibrosis-promoting cytokines, secretion of collagen I were detected with western blot, Real Time PCR and ELISA. Lysate from HSC-T6 cells pretreated with PD98059, a specific MEK1 pharmacological inhibitor, was subjected to detect Hif-1α ubiquitination and nuclear translocation with western blot and immunoprecipitation. Results and Conclusions Hif-1α apparently increased in liver tissues of Schistosomajaponicum infected mice. 1% O2 induced F-actin reorganization, increase of Hif-1α, vimentin and α-SMA in HSC-T6 cells. Hif-1α Knockdown inhibited HSC-T6 activation, transcription of IL-6, TGF-β and CTGF and secretion of collagen I from HSC-T6 cells upon hypoxia. Inhibition of MAPK phosphorylation enhanced Hif-1α ubiquitination, and inhibited Hif-1α translocation into nucleus. Conclusively, Hif-1α and MAPK participate in HSC activation upon hypoxia. PMID:24040163

  4. Rethinking Factors

    ERIC Educational Resources Information Center

    Feldman, Ziv

    2014-01-01

    This article describes an exciting exploration-based activity in which students develop an alternative definition of factor that can help them solve problems like the one presented above. Students work in groups to collect data, analyze the data to make conjectures, and then spend a significant amount of time debating and justifying their…

  5. Behavioral factors.

    PubMed

    Zero, D T; Lussi, A

    2006-01-01

    During and after an erosive challenge, behavioral factors play a role in modifying the extent of erosive tooth wear. The manner that dietary acids are introduced into the mouth (gulping, sipping, use of a straw) will affect how long the teeth are in contact with the erosive challenge. The frequency and duration of exposure to an erosive agent is of paramount importance. Night-time exposure (e.g. baby bottle-feeding) to erosive agents may be particularly destructive because of the absence of salivary flow. Health-conscious individuals tend to ingest acidic drinks and juices more frequently and tend to have higher than average oral hygiene. While good oral hygiene is of proven value in the prevention of periodontal disease and dental caries, frequent toothbrushing with abrasive oral hygiene products may enhance erosive tooth wear. Unhealthy lifestyles such as consumption of designer drugs, alcopops and alcohol abuse are other important behavioral factors.

  6. The Integrative Studies of Genetic and Environmental Factors in Systemic Sclerosis

    DTIC Science & Technology

    2011-05-01

    same results. Notably, increased hair follicles were incon- sistently seen in Ctgf siRNA- and SPARC siRNA-treated bleomycin-induced skins. The lung...scalar covariate part (Xi). Together with previously modeled functional response variable, we have the function regression model like: If we can test ...FDA” package to do permutation F test on PCR vs. SNPs data, which is a reliable statistical test to render a legitimate significance P-value. Since

  7. The Integrative Studies of Genetic and Environmental Factors in Systemic Sclerosis

    DTIC Science & Technology

    2009-05-01

    trichrome staining of the samples also showed the same results. Notably, increased hair follicles were inconsistently seen in Ctgf siRNA- and Sparc siRNA...Real-Time PCR System in Caucasian, African American and Hispanic populations. Genotyping results of all five SNPs passed quality tests for Hardy...by the comparison of minor allele frequencies of the cases and controls, with significance determined by p-values of chi-square tests , Cochran

  8. The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways

    SciTech Connect

    Bordonaro, Michael Tewari, Shruti Atamna, Wafa Lazarova, Darina L.

    2011-06-10

    Unlike the well-characterized nuclear function of the Notch intracellular domain, it has been difficult to identify a nuclear role for the ligands of Notch. Here we provide evidence for the nuclear function of the Notch ligand Delta-like 1 in colon cancer (CC) cells exposed to butyrate. We demonstrate that the intracellular domain of Delta-like 1 (Dll1icd) augments the activity of Wnt signaling-dependent reporters and that of the promoter of the connective tissue growth factor (CTGF) gene. Data suggest that Dll1icd upregulates CTGF promoter activity through both direct and indirect mechanisms. The direct mechanism is supported by co-immunoprecipitation of endogenous Smad2/3 proteins and Dll1 and by chromatin immunoprecipitation analyses that revealed the occupancy of Dll1icd on CTGF promoter sequences containing a Smad binding element. The indirect upregulation of CTGF expression by Dll1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF. CTGF expression is induced in butyrate-treated CC cells and results from clonal growth assays support a role for CTGF in the cell growth-suppressive role of butyrate. In conclusion, integration of the Notch, Wnt, and TGFbeta/Activin signaling pathways is in part mediated by the interactions of Dll1 with Smad2/3 and Tcf4.

  9. Palabras clave SmokefreeTXT | Smokefree Español

    Cancer.gov

    Reciba gratuitamente estímulos para dejar de fumar, consejos y recomendaciones 24 horas al día, los 7 días de la semana en su celular con SmokefreeTXT en Español. Envíe LIBRE al 47848 para suscríbirse.

  10. Heart disease - risk factors

    MedlinePlus

    Heart disease - prevention; CVD - risk factors; Cardiovascular disease - risk factors; Coronary artery disease - risk factors; CAD - risk ... a certain health condition. Some risk factors for heart disease you cannot change, but some you can. ...

  11. Coagulation Factors Test

    MedlinePlus

    ... this page helpful? Also known as: Factor Assays; Blood Clotting Factors; Clotting Factors [or by the individual factor ... person has enough coagulation activity to control the blood clotting process. It is used by healthcare practitioners to ...

  12. Factor VII deficiency

    MedlinePlus

    ... if one or more of these factors are missing or are not functioning like they should. Factor VII is one such coagulation factor. Factor VII deficiency runs in families (inherited) and is very rare. Both parents must ...

  13. Factor II deficiency

    MedlinePlus

    ... if one or more of these factors are missing or are not functioning like they should. Factor II is one such coagulation factor. Factor II deficiency runs in families (inherited) and is very rare. Both parents must ...

  14. Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers

    SciTech Connect

    Hatakeyama, Hiroto; Wu, Sherry Y.; Lyons, Yasmin A.; Pradeep, Sunila; Wang, Wanqin; Huang, Qian; Court, Karem A.; Liu, Tao; Nie, Song; Rodriguez-Aguayo, Cristian; Shen, Fangrong; Huang, Yan; Hisamatsu, Takeshi; Mitamura, Takashi; Jennings, Nicholas; Shim, Jeajun; Dorniak, Piotr L.; Mangala, Lingegowda S.; Petrillo, Marco; Petyuk, Vladislav A.; Schepmoes, Athena A.; Shukla, Anil K.; Torres-Lugo, Madeline; Lee, Ju-Seog; Rodland, Karin D.; Fagotti, Anna; Lopez-Berestein, Gabriel; Li, Chun; Sood, Anil K.

    2016-11-01

    Therapeutic hyperthermia involves raising the temperature of a tumor tissue to 40–43°C. It has been used for treatment of ovarian and other cancers. The rationale for this therapy is based on the direct-killing effects of temperatures above 41-42°C (Wust et al., 2002). Hyperthermia is also applied as an adjunctive therapy with various established cancer treatments, such as radiotherapy and chemotherapy, to sensitize cancers to their effects (Moyer and Delman, 2008; Nagata et al., 1997; Palazzi et al., 2010). Some studies suggested that hyperthermia activates the immune systems against tumor cells by increasing the release of heat shock proteins (HSPs) associated with tumor-specific antigens from heat-stressed or dying tumor cells that are phagocytized by antigen-presenting cells (APCs) (Binder et al., 2000). As interest in hyperthermic treatment of cancer has increased, researchers have made significant progress in developing strategies to heat tumors via local, regional, and whole-body hyperthermia with advancements in surgical techniques, equipment, and nanotechnology (van der Zee, 2002). In localized hyperthermia, heat is applied to a small area restricted to the tumor using various techniques that deliver energy for heating. Different types of energy may be used, including microwaves and radio waves (Gazelle et al., 2000; Seki et al., 1999), magnetic heating (Lee et al., 2011; Rodriguez-Luccioni et al., 2011), and ultrasound (Jolesz and Hynynen, 2002). Regional hyperthermia is applied via perfusion of a limb, organ, or body cavity with heated fluids. For example, the intraperitoneal route of heated chemotherapy administration (hyperthermic intraperitoneal chemotherapy [HIPEC]), which usually lasts 60-120 min with continuous cycling of the chemotherapeutic agent at 42°C, enables direct contact between the tumor cells and the chemotherapeutic agent to control all residual microscopic disease, including microscopic ovarian cancers (Jinny Ha, 2012). Even though hyperthermia is a promising improvement of cancer treatment, multiple obstacles remain to be cleared. One of the major issues is that the tumor temperatures that must be reached for obtaining clinical efficacy are undefined (Wust et al., 2002). In the present study, we monitored the temperature transition in tumors during HIPEC in ovarian cancer patients (Figure S1). Even though the perfusion temperature at the entrance was maintained at 42.5°C, the temperature in most of the tumors was about 40°C, which is the temperature seen with just a high fever, and the clinical benefit of these lower temperatures was unclear. Also, no data on predictors of sensitivity of ovarian and uterine tumors to hyperthermia has been addressed. The purpose of the present study was to determine the molecular mechanism of response of gynecological cancer cells to hyperthermia. We hypothesized that inhibition of a critical gene of hyperthermia resistance by small interfering RNA (siRNA) can sensitize ovarian and uterine cancers to hyperthermia. To achieve this, we explored the genes that regulate hyperthermia resistance by comparing gene and protein expression between hyperthermia sensitive and resistant cells. We performed that silencing of the novel target gene could sensitize hyperthermia resistant cancer cells to hyperthermic treatment both in vitro and orthotopic ovarian cancer models in vivo with copper sulfate nanoparticles and near-infrared laser treatment.

  15. [Subtypes of mild cognitive impairment in Parkinson's disease and factors predicting its becoming dementia].

    PubMed

    Toribio-Diaz, M Elena; Carod-Artal, Francisco J

    2015-07-01

    Introduccion. El deterioro cognitivo puede aparecer en las etapas mas iniciales de la enfermedad de Parkinson (EP). Determinar la prevalencia del deterioro cognitivo leve (DCL) como etapa de transicion o sus diferentes perfiles resulta complicado por la ausencia de criterios diagnosticos consensuados. Objetivo. Revisar el concepto de DCL en la EP, sus criterios diagnosticos y los factores predictores de conversion a demencia. Pacientes y metodos. Revision sistematica de los articulos publicados en Medline (PubMed) utilizando la combinacion de las palabras clave 'deterioro cognitivo leve' y 'enfermedad de Parkinson'. Resultados. Los criterios diagnosticos del DCL en la EP publicados por la Sociedad de Trastornos del Movimiento, a pesar de no estar validados, constituyen una importante herramienta para el diagnostico de estos pacientes. Su aplicacion se ve influida por las siguientes limitaciones: la heterogeneidad de los deficits cognitivos descritos en la EP, su evolucion variable, que dificulta el hallazgo de factores predictores de conversion a demencia, la seleccion de las pruebas neuropsicologicas mas apropiadas y la determinacion de los puntos de corte mas idoneos, y las caracteristicas del paciente, etapa de la enfermedad y tipo de tratamiento antiparkinsoniano. Conclusiones. Marcadores neuropsicologicos, de neuroimagen, biomarcadores o la limitacion en algunas actividades instrumentales son muy prometedores para la deteccion de pacientes con DCL en la EP y riesgo elevado de conversion a demencia.

  16. Constructivism, Factoring, and Beliefs.

    ERIC Educational Resources Information Center

    Rauff, James V.

    1994-01-01

    Discusses errors made by remedial intermediate algebra students in factoring polynomials in light of student definitions of factoring. Found certain beliefs about factoring to logically imply many of the errors made. Suggests that belief-based teaching can be successful in teaching factoring. (16 references) (Author/MKR)

  17. Resolution with Limited Factoring

    NASA Astrophysics Data System (ADS)

    Li, Dafa

    The resolution principle was originally proposed by J.A. Robinson. Resolution with factoring rule is complete for the first-order logic. However, unlimited applications of factoring rule may generate many irrelevant and redundant clauses. Noll presented resolution rule with half-factoring. In this paper, we demonstrate how to eliminate the half-factoring.

  18. Psychological factors affecting migraine.

    PubMed

    Shulman, B H

    1989-01-01

    Psychological factors are known to increase the severity and intensity of headaches. When they are shown to be present, an appropriate psychiatric diagnosis is the Diagnostic and Statistical Manual's (DSMIII-R) category of psychological factors affecting physical condition (code no. 316.0). These factors can be differentiated into stress factors, personality traits, psychodynamic factors, learned behaviors, and mood disturbances. The factors overlap and intertwine in the average headache patient. Attention to these factors in a systematic way should enhance our understanding and treatment of the chronic headache patient.

  19. ISS Payload Human Factors

    NASA Technical Reports Server (NTRS)

    Ellenberger, Richard; Duvall, Laura; Dory, Jonathan

    2016-01-01

    The ISS Payload Human Factors Implementation Team (HFIT) is the Payload Developer's resource for Human Factors. HFIT is the interface between Payload Developers and ISS Payload Human Factors requirements in SSP 57000. ? HFIT provides recommendations on how to meet the Human Factors requirements and guidelines early in the design process. HFIT coordinates with the Payload Developer and Astronaut Office to find low cost solutions to Human Factors challenges for hardware operability issues.

  20. Activation of human factor IX (Christmas factor).

    PubMed Central

    Di Scipio, R G; Kurachi, K; Davie, E W

    1978-01-01

    Human Factor IX (Christmas factor) is a single-chain plasma glycoprotein (mol wt 57,000) that participates in the middle phase of the intrinsic pathway of blood coagulation. It is present in plasma as a zymogen and is converted to a serine protease, Factor IXabeta, by Factor XIa (activated plasma thromboplastin antecedent) in the presence of calcium ions. In the activation reaction, two internal peptide bonds are hydrolyzed in Factor IX. These cleavages occur at a specific arginyl-alanine peptide bond and a specific arginyl-valine peptide bond. This results in the release of an activation peptide (mol wt approximately equal to 11,000) from the internal region of the precursor molecule and the generation of Factor IXabeta (mol wt approximately equal to 46,000). Factor IXabeta is composed of a light chain (mol wt approximately equal to 18,000) and a heavy chain (mol wt approximately equal to 28,000), and these chains are held together by a disulfide bond(s). The light chain originates from the amino terminal portion of the precursor molecule and has an amino terminal sequence of Tyr-Asn-Ser-Gly-Lys. The heavy chain originates from the carboxyl terminal region of the precursor molecule and contains an amino terminal sequence of Val-Val-Gly-Gly-Glu. The heavy chain of Factor IXabeta also contains the active site sequence of Phe-Cys-Ala-Gly-Phe-His-Glu-Gly-Arg-Asp-Ser-Cys-Gln-Gly-Asp-SER-Gly-Gly-Pro. The active site serine residue is shown in capital letters. Factor IX is also converted to Factor IXaalpha by a protease from Russell's viper venom. This activation reaction, however, occurs in a single step and involves only the cleavage of the internal arginyl-valine peptide bond. Human Factor IXabeta was inhibited by human antithrombin III by the formation of a one-to-one complex of enzyme and inhibitor. In this reaction, the inhibitor was tightly bound to the heavy chain of the enzyme. These data indicate that the mechanism of activation of human Factor IX and its

  1. Factoring Polynomials and Fibonacci.

    ERIC Educational Resources Information Center

    Schwartzman, Steven

    1986-01-01

    Discusses the factoring of polynomials and Fibonacci numbers, offering several challenges teachers can give students. For example, they can give students a polynomial containing large numbers and challenge them to factor it. (JN)

  2. Factor V deficiency

    MedlinePlus

    ... as many as 20 different proteins in blood plasma. These proteins are called blood coagulation factors. Factor ... You will be given fresh blood plasma or fresh frozen plasma infusions ... These treatments will correct the deficiency temporarily.

  3. Prognostic factors in cancer.

    PubMed

    Gospodarowicz, Mary; O'Sullivan, Brian

    2003-01-01

    Diagnosis, prognosis, and treatment are the three core elements of the art of medicine. Modern medicine pays more attention to diagnosis and treatment but prognosis has been a part of the practice of medicine much longer than diagnosis. Cancer is a heterogeneous group of disease characterized by growth, invasion and metastasis. To plan the management of an individual cancer patient, the fundamental knowledge base includes the site of origin of the cancer, its morphologic type, and the prognostic factors specific to that particular patient and cancer. Most prognostic factors literature describes those factors that directly relate to the tumor itself. However, many other factors, not directly related to the tumor, also affect the outcome. To comprehensively represent these factors we propose three broad groupings of prognostic factors: 'tumor'-related prognostic factors, 'host'-related prognostic factors, and 'environment'-related prognostic factors. Some prognostic factors are essential to decisions about the goals and choice treatment, while others are less relevant for these purposes. To guide the use of various prognostic factors we have proposed a grouping of factors based on their relevance in everyday practice; these comprise 'essential,' 'additional,' and 'new and promising factors.' The availability of a comprehensive classification of prognostic factors assures an ordered and deliberate approach to the subject and provide safeguard against skewed approaches that may ignore large parts of the field. The current attention to tumor factors has diminished the importance of 'patient' (i.e., 'host'), and almost completely overshadows the importance of the 'environment'. This ignores the fact that the latter presents the greatest potential for immediate impact. The acceptance of a generic prognostic factor classification would facilitate communication and education about this most important subject in oncology.

  4. Rh Factor Blood Test

    MedlinePlus

    Tests and Procedures Rh factor blood test By Mayo Clinic Staff Rhesus (Rh) factor is an inherited protein found on the surface of red ... positive. Your health care provider will recommend an Rh factor test during your first prenatal visit. This test ...

  5. A Factor Simplicity Index.

    ERIC Educational Resources Information Center

    Lorenzo-Seva, Urbano

    2003-01-01

    Proposes an index for assessing the degree of factor simplicity in the context of principal components and exploratory factor analysis. The index does not depend on the scale of the factors, and its maximum and minimum are related only to the degree of simplicity in the loading matrix. (SLD)

  6. Aerostructural safety factor criteria

    NASA Technical Reports Server (NTRS)

    Verderaime, V.

    1992-01-01

    The present modification of the conventional safety factor method for aircraft structures evaluation involves the expression of deterministic safety factors in probabilistic tolerance limit ratios; these are found to involve a total of three factors that control the interference of applied and resistive stress distributions. The deterministic expression is extended so that it may furnish a 'relative ultimate safety' index that encompasses all three distribution factors. Operational reliability is developed on the basis of the applied and the yield stress distribution interferences. Industry standards are suggested to be derivable from factor selections that are based on the consequences of failure.

  7. Acquired Factor V Inhibitor

    PubMed Central

    Hirai, Daisuke; Yamashita, Yugo; Masunaga, Nobutoyo; Katsura, Toshiaki; Akao, Masaharu; Okuno, Yoshiaki; Koyama, Hiroshi

    2016-01-01

    Inhibitors directed against factor V rarely occur, and the clinical symptoms vary. We herein report the case of a patient who presented with a decreased factor V activity that had decreased to <3 %. We administered vitamin K and 6 units of fresh frozen plasma, but she thereafter developed an intracerebral hemorrhage. It is unclear whether surgery >10 years earlier might have caused the development of a factor V inhibitor. The treatment of acquired factor V inhibitors is mainly the transfusion of platelet concentrates and corticosteroids. Both early detection and the early initiation of the treatment of factor V inhibitor are thus considered to be important. PMID:27746446

  8. Bayesian Exploratory Factor Analysis

    PubMed Central

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J.; Piatek, Rémi

    2014-01-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates from a high dimensional set of psychological measurements. PMID:25431517

  9. Graphical mass factorization

    NASA Astrophysics Data System (ADS)

    Humpert, B.; van Neerven, W. L.

    1981-07-01

    We point to the close analogy between (multiplicative) BPHZ-renormalization and mass factorization. Adapation of the forest formula to mass singular graphs allows an alternative proof of mass factorization. A diagrammatic method is developed to carry out diagram-by-diagram mass factorization with the mass singularities being subtracted by counter terms which built up the operator matrix element. The reasoning is exposed for deep-inelastic (DI) scattering and for the Drell-Yan (DY) process.

  10. Oversimplifying quantum factoring.

    PubMed

    Smolin, John A; Smith, Graeme; Vargo, Alexander

    2013-07-11

    Shor's quantum factoring algorithm exponentially outperforms known classical methods. Previous experimental implementations have used simplifications dependent on knowing the factors in advance. However, as we show here, all composite numbers admit simplification of the algorithm to a circuit equivalent to flipping coins. The difficulty of a particular experiment therefore depends on the level of simplification chosen, not the size of the number factored. Valid implementations should not make use of the answer sought.

  11. [Acquired coagulant factor inhibitors].

    PubMed

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  12. Analytic Couple Modeling Introducing Device Design Factor, Fin Factor, Thermal Diffusivity Factor, and Inductance Factor

    NASA Technical Reports Server (NTRS)

    Mackey, Jon; Sehirlioglu, Alp; Dynys, Fred

    2014-01-01

    A set of convenient thermoelectric device solutions have been derived in order to capture a number of factors which are previously only resolved with numerical techniques. The concise conversion efficiency equations derived from governing equations provide intuitive and straight-forward design guidelines. These guidelines allow for better device design without requiring detailed numerical modeling. The analytical modeling accounts for factors such as i) variable temperature boundary conditions, ii) lateral heat transfer, iii) temperature variable material properties, and iv) transient operation. New dimensionless parameters, similar to the figure of merit, are introduced including the device design factor, fin factor, thermal diffusivity factor, and inductance factor. These new device factors allow for the straight-forward description of phenomenon generally only captured with numerical work otherwise. As an example a device design factor of 0.38, which accounts for thermal resistance of the hot and cold shoes, can be used to calculate a conversion efficiency of 2.28 while the ideal conversion efficiency based on figure of merit alone would be 6.15. Likewise an ideal couple with efficiency of 6.15 will be reduced to 5.33 when lateral heat is accounted for with a fin factor of 1.0.

  13. Exploratory Bi-Factor Analysis

    ERIC Educational Resources Information Center

    Jennrich, Robert I.; Bentler, Peter M.

    2011-01-01

    Bi-factor analysis is a form of confirmatory factor analysis originally introduced by Holzinger. The bi-factor model has a general factor and a number of group factors. The purpose of this article is to introduce an exploratory form of bi-factor analysis. An advantage of using exploratory bi-factor analysis is that one need not provide a specific…

  14. Overview of environmental factors

    NASA Technical Reports Server (NTRS)

    Purvis, C. K.

    1989-01-01

    The orbital environment is complex, dynamic, and comprised of both natural and system-induced components. Several environment factors are important for materials. Materials selection/suitability determination requires consideration of each and all factors, including synergisms among them. Understanding and evaluating these effects will require ground testing, modeling, and focused flight experimentation.

  15. Exposure Factors Handbook Chapter 16

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  16. Exposure Factors Handbook Chapter 18

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  17. Exposure Factors Handbook Chapter 14

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  18. Exposure Factors Handbook Chapter 15

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  19. Exposure Factors Handbook Chapter 6

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  20. Exposure Factors Handbook Chapter 10

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  1. Exposure Factors Handbook Chapter 9

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  2. Exposure Factors Handbook Chapter 13

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  3. Exposure Factors Handbook (2011 Edition)

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  4. Exposure Factors Handbook Chapter 8

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  5. Exposure Factors Handbook Chapter 5

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  6. Exposure Factors Handbook Chapter 3

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  7. Exposure Factors Handbook Chapter 17

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  8. Exposure Factors Handbook Chapter 2

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  9. Exposure Factors Handbook Chapter 12

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  10. Exposure Factors Handbook Chapter 11

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  11. Exposure Factors Handbook Chapter 7

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  12. Exposure Factors Handbook Chapter 19

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  13. Exposure Factors Handbook Chapter 1

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  14. Exposure Factors Handbook Chapter 4

    EPA Pesticide Factsheets

    Exposure Factors Handbook: 2011 Edition. The Exposure Factors Handbook provides information on various physiological and behavioral factors commonly used in assessing exposure to environmental chemicals.

  15. [Dyslipidemias in school-age chilean children: prevalence and associated factors].

    PubMed

    Barja Yáñez, Salesa; Arnaiz Gómez, Pilar; Villarroel Del Pino, Luis; Domínguez de Landa, Angélica; Castillo Valenzuela, Oscar; Farías Jofré, Marcelo; Mardones Santander, Francisco

    2015-05-01

    Introducción: Las dislipidemias son un factor de riesgo cardiovascular clave, en aumento ya desde la niñez. El objetivo de este estudio fue describir la prevalencia, tipo de dislipidemias y factores asociados, en una población de niños chilenos. Métodos: Estudio transversal en escolares de Santiago de Chile (2009-2011). Se realizó antropometría, encuesta de antecedentes familiares a los padres y de actividad física a los niños. En muestra sanguínea de ayunas se midió perfil lipídico, glicemia e insulinemia. Resultados: Se reclutaron 2900 escolares de 11,42±0,97 años de edad, 52% mujeres, todos euglicémicos. Según IMC, 22,5% tenía sobrepeso y 15,3% obesidad. Al considerar los límites recomendados para cada lípido, 69,3% se encontraba en rango aceptable, 19,2% en riesgo y 11,5% en alto riesgo cardiovascular. En total, 32% de la población presentó alguna forma clínica de dislipidemia: Hipertrigliceridemia aislada (9,4%), Bajo C-HDL (7,6%), Hipercolesterolemia aislada (4,9%), Dislipidemia aterogénica (6,24%) y Dislipidemia mixta (3,9%). Excepto la hipercolesterolemia aislada, las demás dislipidemias fueron más frecuentes en las niñas (36,2% vs. 27,4%, p.

  16. Risk Factors for Tuberculosis

    PubMed Central

    Narasimhan, Padmanesan; Wood, James; MacIntyre, Chandini Raina; Mathai, Dilip

    2013-01-01

    The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli. PMID:23476764

  17. Environmental factors in autism.

    PubMed

    Grabrucker, Andreas M

    2012-01-01

    Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed.

  18. Factorized Graph Matching.

    PubMed

    Zhou, Feng; de la Torre, Fernando

    2015-11-19

    Graph matching (GM) is a fundamental problem in computer science, and it plays a central role to solve correspondence problems in computer vision. GM problems that incorporate pairwise constraints can be formulated as a quadratic assignment problem (QAP). Although widely used, solving the correspondence problem through GM has two main limitations: (1) the QAP is NP-hard and difficult to approximate; (2) GM algorithms do not incorporate geometric constraints between nodes that are natural in computer vision problems. To address aforementioned problems, this paper proposes factorized graph matching (FGM). FGM factorizes the large pairwise affinity matrix into smaller matrices that encode the local structure of each graph and the pairwise affinity between edges. Four are the benefits that follow from this factorization: (1) There is no need to compute the costly (in space and time) pairwise affinity matrix; (2) The factorization allows the use of a path-following optimization algorithm, that leads to improved optimization strategies and matching performance; (3) Given the factorization, it becomes straight-forward to incorporate geometric transformations (rigid and non-rigid) to the GM problem. (4) Using a matrix formulation for the GM problem and the factorization, it is easy to reveal commonalities and differences between different GM methods. The factorization also provides a clean connection with other matching algorithms such as iterative closest point; Experimental results on synthetic and real databases illustrate how FGM outperforms state-of-the-art algorithms for GM. The code is available at http://humansensing.cs.cmu.edu/fgm.

  19. Environmental Factors in Autism

    PubMed Central

    Grabrucker, Andreas M.

    2013-01-01

    Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed. PMID:23346059

  20. Conundrums with uncertainty factors.

    PubMed

    Cooke, Roger

    2010-03-01

    The practice of uncertainty factors as applied to noncancer endpoints in the IRIS database harkens back to traditional safety factors. In the era before risk quantification, these were used to build in a "margin of safety." As risk quantification takes hold, the safety factor methods yield to quantitative risk calculations to guarantee safety. Many authors believe that uncertainty factors can be given a probabilistic interpretation as ratios of response rates, and that the reference values computed according to the IRIS methodology can thus be converted to random variables whose distributions can be computed with Monte Carlo methods, based on the distributions of the uncertainty factors. Recent proposals from the National Research Council echo this view. Based on probabilistic arguments, several authors claim that the current practice of uncertainty factors is overprotective. When interpreted probabilistically, uncertainty factors entail very strong assumptions on the underlying response rates. For example, the factor for extrapolating from animal to human is the same whether the dosage is chronic or subchronic. Together with independence assumptions, these assumptions entail that the covariance matrix of the logged response rates is singular. In other words, the accumulated assumptions entail a log-linear dependence between the response rates. This in turn means that any uncertainty analysis based on these assumptions is ill-conditioned; it effectively computes uncertainty conditional on a set of zero probability. The practice of uncertainty factors is due for a thorough review. Two directions are briefly sketched, one based on standard regression models, and one based on nonparametric continuous Bayesian belief nets.

  1. Factors Influencing Army Maintenance

    DTIC Science & Technology

    1989-01-01

    ARI Research Note 89-11 (N 00 Factors Influencing Army Maintenance LOloD Debra C. Evans and J. Thomas Roth Applied Science Associates, Inc. for...1.2.7 .2.7.C.1 11. TITLE (Include Security ClassifIcarIon) Factors Influencing Army Maintenance i2. FERSONAL AuTtiOR(S) Evans, Debra C., and Roth, J...y • ’ Factors and variables that influence maintenance for systems and related manpower, per- sonnel, and training (MPT) characteristics were

  2. Introduction to human factors.

    PubMed

    Bergman, Eric

    2012-03-01

    This paper provides an introduction to "human factors engineering," an applied science that seeks to optimize usability and safety of systems. Human factors engineering pursues this goal by aligning system design with the perceptual, cognitive, and physical capabilities of users. Human factors issues loom large in the diabetes management domain because patients and health care professionals interact with a complex variety of systems, including medical device hardware and software, which are themselves embedded within larger systems of institutions, people, and processes. Usability considerations must be addressed in these systems and devices to ensure safe and effective diabetes management.

  3. Scaling factors: transcription factors regulating subcellular domains.

    PubMed

    Mills, Jason C; Taghert, Paul H

    2012-01-01

    Developing cells acquire mature fates in part by selective (i.e. qualitatively different) expression of a few cell-specific genes. However, all cells share the same basic repertoire of molecular and subcellular building blocks. Therefore, cells must also specialize according to quantitative differences in cell-specific distributions of those common molecular resources. Here we propose the novel hypothesis that evolutionarily-conserved transcription factors called scaling factors (SFs) regulate quantitative differences among mature cell types. SFs: (1) are induced during late stages of cell maturation; (2) are dedicated to specific subcellular domains; and, thus, (3) allow cells to emphasize specific subcellular features. We identify candidate SFs and discuss one in detail: MIST1 (BHLHA15, vertebrates)/DIMM (CG8667, Drosophila); professional secretory cells use this SF to scale up regulated secretion. Because cells use SFs to develop their mature properties and also to adapt them to ever-changing environmental conditions, SF aberrations likely contribute to diseases of adult onset.

  4. Factors affecting bone growth.

    PubMed

    Gkiatas, Ioannis; Lykissas, Marios; Kostas-Agnantis, Ioannis; Korompilias, Anastasios; Batistatou, Anna; Beris, Alexandros

    2015-02-01

    Bone growth and development are products of the complex interactions of genetic and environmental factors. Longitudinal bone growth depends on the growth plate. The growth plate has 5 different zones-each with a different functional role-and is the final target organ for longitudinal growth. Bone length is affected by several systemic, local, and mechanical factors. All these regulation systems control the final length of bones in a complicated way. Despite its significance to bone stability, bone growth in width has not been studied as extensively as longitudinal bone growth. Bone growth in width is also controlled by genetic factors, but mechanical loading regulates periosteal apposition. In this article, we review the most recent data regarding bone growth from the embryonic age and analyze the factors that control bone growth. An understanding of this complex system is important in identifying metabolic and developmental bone diseases and fracture risk.

  5. New microbial growth factor

    NASA Technical Reports Server (NTRS)

    Bok, S. H.; Casida, L. E., Jr.

    1977-01-01

    A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a previously unknown microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight and has high specific activity. When added to the diets for a meadow-vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain.

  6. Risk Factors and Prevention

    MedlinePlus

    ... atherosclerosis (“clogged” arteries) and High Blood Pressure . Preventing Arrhythmias and Heart Disease Prevent heart disease by lowering ... cholesterol, diabetes, and thyroid disease. Risk Factors For Arrhythmias and Heart Disease The following conditions can increase ...

  7. Factor XII assay

    MedlinePlus

    ... D, Neff AT. Rare coagulation factor deficiencies. In: Hoffman R, Benz EJ Jr, Silberstein LE, Heslop HE, ... Laboratory evaluation of hemostatic and thrombotic disorders. In: Hoffman R, Benz EJ Jr, Silberstein LE, Heslop HE, ...

  8. Sleep regulatory factors.

    PubMed

    Porkka-Heiskanen, T

    2014-01-01

    The state of sleep consists of different phases that proceed in successive, tightly regulated order through the night forming a physiological program, which for each individual is different but stabile from one night to another. Failure to accomplish this program results in feeling of unrefreshing sleep and tiredness in the morning. The pro- gram core is constructed by genetic factors but regulated by circadian rhythm and duration and intensity of day time brain activity. Many environmental factors modulate sleep, including stress, health status and ingestion of vigilance-affecting nutrients or medicines (e.g. caffeine). Knowledge of the factors that regulate the spontaneous sleep-wake cycle and factors that can affect this regulation forms the basis for diagnosis and treatment of the many common disorders of sleep.

  9. Aerospace Human Factors

    NASA Technical Reports Server (NTRS)

    Jordan, Kevin

    1999-01-01

    The following contains the final report on the activities related to the Cooperative Agreement between the human factors research group at NASA Ames Research Center and the Psychology Department at San Jose State University. The participating NASA Ames division has been, as the organization has changed, the Aerospace Human Factors Research Division (ASHFRD and Code FL), the Flight Management and Human Factors Research Division (Code AF), and the Human Factors Research and Technology Division (Code IH). The inclusive dates for the report are November 1, 1984 to January 31, 1999. Throughout the years, approximately 170 persons worked on the cooperative agreements in one capacity or another. The Cooperative Agreement provided for research personnel to collaborate with senior scientists in ongoing NASA ARC research. Finally, many post-MA/MS and post-doctoral personnel contributed to the projects. It is worth noting that 10 former cooperative agreement personnel were hired into civil service positions directly from the agreements.

  10. FGF growth factor analogs

    DOEpatents

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  11. CATTELL AND EYSENCK FACTOR SCORES RELATED TO COMREY PERSONALITY FACTORS.

    PubMed

    Comrey, A L; Duffy, K E

    1968-10-01

    The Eysenck Personality Inventory, the Cattell 16 PF Inventory, and the Comrey Personality Inventory were administered to 272 volunteers. Eysenck and Cattell factor scores were correlated with scores over homogeneous item groups (FHIDs) which define the Comrey test factors. This matrix was factor analyzed to relate the Eysenck and Cattell factor scores to the factor structure underlying the Comrey test. The Eysenck Neuroticism, Comrey Neuroticism, and Cattell second-order Anxiety factors appeared to match. The Eysenck Introversion and the Comrey Shyness factors also matched. The 16 Cattell primary factors overlapped but did not match with the Comrey factors.

  12. Factor Loading Estimation Error and Stability Using Exploratory Factor Analysis

    ERIC Educational Resources Information Center

    Sass, Daniel A.

    2010-01-01

    Exploratory factor analysis (EFA) is commonly employed to evaluate the factor structure of measures with dichotomously scored items. Generally, only the estimated factor loadings are provided with no reference to significance tests, confidence intervals, and/or estimated factor loading standard errors. This simulation study assessed factor loading…

  13. Breast cancer risk factors

    PubMed Central

    Ciszewski, Tomasz; Łopacka-Szatan, Karolina; Miotła, Paweł; Starosławska, Elżbieta

    2015-01-01

    Breast cancer is the most frequently diagnosed neoplastic disease in women around menopause often leading to a significant reduction of these women's ability to function normally in everyday life. The increased breast cancer incidence observed in epidemiological studies in a group of women actively participating in social and professional life implicates the necessity of conducting multidirectional studies in order to identify risk factors associated with the occurrence of this type of neoplasm. Taking the possibility of influencing the neoplastic transformation process in individuals as a criterion, all the risk factors initiating the process can be divided into two groups. The first group would include inherent factors such as age, sex, race, genetic makeup promoting familial occurrence of the neoplastic disease or the occurrence of benign proliferative lesions of the mammary gland. They all constitute independent parameters and do not undergo simple modification in the course of an individual's life. The second group would include extrinsic factors conditioned by lifestyle, diet or long-term medical intervention such as using oral hormonal contraceptives or hormonal replacement therapy and their influence on the neoplastic process may be modified to a certain degree. Identification of modifiable factors may contribute to development of prevention strategies decreasing breast cancer incidence. PMID:26528110

  14. [Prognostic factors in resuscitation].

    PubMed

    Bahloul, F; Le Gall, J R; Loirat, P; Alperovitch, A; Patois, E

    1988-10-08

    The outcome from intensive care is known to be influenced by such factors as age, previous health status, severity of the disease and diagnosis. In order to assess the influence of each individual factor, 3,687 patients from 38 French intensive care units were studied. For each patient were recorded: age, simplified acute physiological score (SAPS), previous health status, diagnosis, type of intensive care unit (medicine, scheduled or elective surgery) and immediate outcome. Each of these factors was found to influence the immediate survival rate. A multivariate analysis ranked the factors in the following order: SAPS, age, type of intensive care unit and previous health status. Diagnosis played a role in the prognosis since with a 10-15 points SAPS mortality was nil for drug overdose, 12 per cent for chronic obstructive pulmonary disease and 38 per cent for cardiogenic shock. However, a single diagnosis was made in only 37 per cent of the patients, as against 3 diagnoses in 17 per cent and 4 diagnoses or more in 7 per cent. When the type of intensive care unit was considered, the mean death rate was 20 per cent in medicine, 27 per cent in scheduled surgery and 5 per cent in elective surgery (P less than 0.001). Since this study showed a definite influence of each of the four factors on immediate survival, intensive care patients can be described and classified according to this system. However, it must be stressed that individual prognoses are extremely vague.

  15. A load factor formula

    NASA Technical Reports Server (NTRS)

    Miller, Roy G

    1927-01-01

    The ultimate test of a load factor formula is experience. The chief advantages of a semi rational formula over arbitrary factors are that it fairs in between points of experience and it differentiates according to variables within a type. Structural failure of an airplane apparently safe according to the formula would call for a specific change in the formula. The best class of airplanes with which to check a load factor formula seems to be those which have experienced structural failure. Table I comprises a list of the airplanes which have experienced failure in flight traceable to the wing structure. The load factor by formula is observed to be greater than the designed strength in each case, without a single exception. Table II comprises the load factor by formula with the designed strength of a number of well-known service types. The formula indicates that by far the majority of these have ample structural strength. One case considered here in deriving a suitable formula is that of a heavy load carrier of large size and practically no reserve power.

  16. Multi-factor authentication

    DOEpatents

    Hamlet, Jason R; Pierson, Lyndon G

    2014-10-21

    Detection and deterrence of spoofing of user authentication may be achieved by including a cryptographic fingerprint unit within a hardware device for authenticating a user of the hardware device. The cryptographic fingerprint unit includes an internal physically unclonable function ("PUF") circuit disposed in or on the hardware device, which generates a PUF value. Combining logic is coupled to receive the PUF value, combines the PUF value with one or more other authentication factors to generate a multi-factor authentication value. A key generator is coupled to generate a private key and a public key based on the multi-factor authentication value while a decryptor is coupled to receive an authentication challenge posed to the hardware device and encrypted with the public key and coupled to output a response to the authentication challenge decrypted with the private key.

  17. Psychological Factors in Asthma

    PubMed Central

    2008-01-01

    Asthma has long been considered a condition in which psychological factors have a role. As in many illnesses, psychological variables may affect outcome in asthma via their effects on treatment adherence and symptom reporting. Emerging evidence suggests that the relation between asthma and psychological factors may be more complex than that, however. Central cognitive processes may influence not only the interpretation of asthma symptoms but also the manifestation of measurable changes in immune and physiologic markers of asthma. Furthermore, asthma and major depressive disorder share several risk factors and have similar patterns of dysregulation in key biologic systems, including the neuroendocrine stress response, cytokines, and neuropeptides. Despite the evidence that depression is common in people with asthma and exerts a negative impact on outcome, few treatment studies have examined whether improving symptoms of depression do, in fact, result in better control of asthma symptoms or improved quality of life in patients with asthma. PMID:20525122

  18. DSN human factors project

    NASA Technical Reports Server (NTRS)

    Chafin, R. L.; Martin, T. H.

    1980-01-01

    The project plan was to hold focus groups to identify the factors influencing the ease of use characteristics of software and to bond the problem. A questionnaire survey was conducted to evaluate those factors which were more appropriately measured with that method. The performance oriented factors were analyzed and relationships hypothesized. The hypotheses were put to test in the experimental phase of the project. In summary, the initial analysis indicates that there is an initial performance effect favoring computer controlled dialogue but the advantage fades fast as operators become experienced. The user documentation style is seen to have a significant effect on performance. The menu and prompt command formats are preferred by inexperienced operators. The short form mnemonic is least favored. There is no clear best command format but the short form mnemonic is clearly the worst.

  19. Geothermal Plant Capacity Factors

    SciTech Connect

    Greg Mines; Jay Nathwani; Christopher Richard; Hillary Hanson; Rachel Wood

    2015-01-01

    The capacity factors recently provided by the Energy Information Administration (EIA) indicated this plant performance metric had declined for geothermal power plants since 2008. Though capacity factor is a term commonly used by geothermal stakeholders to express the ability of a plant to produce power, it is a term frequently misunderstood and in some instances incorrectly used. In this paper we discuss how this capacity factor is defined and utilized by the EIA, including discussion on the information that the EIA requests from operations in their 923 and 860 forms that are submitted both monthly and annually by geothermal operators. A discussion is also provided regarding the entities utilizing the information in the EIA reports, and how those entities can misinterpret the data being supplied by the operators. The intent of the paper is to inform the facility operators as the importance of the accuracy of the data that they provide, and the implications of not providing the correct information.

  20. Electromagnetic nucleon form factors

    SciTech Connect

    Bender, A.; Roberts, C.D.; Frank, M.R.

    1995-08-01

    The Dyson-Schwinger equation framework is employed to obtain expressions for the electromagnetic nucleon form factor. In generalized impulse approximation the form factor depends on the dressed quark propagator, the dressed quark-photon vertex, which is crucial to ensuring current conservation, and the nucleon Faddeev amplitude. The approach manifestly incorporates the large space-like-q{sup 2} renormalization group properties of QCD and allows a realistic extrapolation to small space-like-q{sup 2}. This extrapolation allows one to relate experimental data to the form of the quark-quark interaction at small space-like-q{sup 2}, which is presently unknown. The approach provides a means of unifying, within a single framework, the treatment of the perturbative and nonperturbative regimes of QCD. The wealth of experimental nucleon form factor data, over a large range of q{sup 2}, ensures that this application will provide an excellent environment to test, improve and extend our approach.

  1. The transcription factor encyclopedia.

    PubMed

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A; Zhang, Xiao Yu Cindy; Dickman, Christopher T D; Fulton, Debra L; Lim, Jonathan S; Schnabl, Jake M; Ramos, Oscar H P; Vasseur-Cognet, Mireille; de Leeuw, Charles N; Simpson, Elizabeth M; Ryffel, Gerhart U; Lam, Eric W-F; Kist, Ralf; Wilson, Miranda S C; Marco-Ferreres, Raquel; Brosens, Jan J; Beccari, Leonardo L; Bovolenta, Paola; Benayoun, Bérénice A; Monteiro, Lara J; Schwenen, Helma D C; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A; Chakravarthy, Harini; Hoodless, Pamela A; Mancarelli, M Michela; Torbett, Bruce E; Banham, Alison H; Reddy, Sekhar P; Cullum, Rebecca L; Liedtke, Michaela; Tschan, Mario P; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J; Eijkelenboom, Astrid; Brown, Philip J; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J; Van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W Z; Breslin, Mary B; Lan, Michael S; Nanan, Kyster K; Wegner, Michael; Hou, Juan; Mullen, Rachel D; Colvin, Stephanie C; Noy, Peter John; Webb, Carol F; Witek, Matthew E; Ferrell, Scott; Daniel, Juliet M; Park, Jason; Waldman, Scott A; Peet, Daniel J; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M; Woodcroft, Mark W; Hough, Margaret R; Chen, Edwin; Europe-Finner, G Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; LeBrun, David P; Biswal, Shyam; Harvey, Christopher J; DeBruyne, Jason P; Hogenesch, John B; Hevner, Robert F; Héligon, Christophe; Luo, Xin M; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M; Bradley, Philip H; Wasserman, Wyeth W

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

  2. Factor D Enzyme

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The trauma caused by the open heart surgery often triggers massive inflammation because the immune system overreacts. Factor D, the protein which plays a key role in the biological steps that activate this immune response prevents the imune system from inappropriately rurning out of control, allowing the patient to recover more rapidly. Factor D blockers, with their great potential to alleviate the complication of inflammation associated with heart surgery, are now being developed for clinical trials. These new drugs, developed from space research, should be commercially available as soon as year 2001.

  3. [Natural factors influencing sleep].

    PubMed

    Jurkowski, Marek K; Bobek-Billewicz, Barbara

    2007-01-01

    Sleep is a universal phenomenon of human and animal lives, although the importance of sleep for homeo-stasis is still unknown. Sleep disturbances influence many behavioral and physiologic processes, leading to health complications including death. On the other hand, sleep improvement can beneficially influence the course of healing of many disorders and can be a prognostic of health recovery. The factors influencing sleep have different biological and chemical origins. They are classical hormones, hypothalamic releasing and inhibitory hormones, neuropeptides, peptides and others as cytokines, prostaglandins, oleamid, adenosine, nitric oxide. These factors regulate most physiologic processes and are likely elements integrating sleep with physiology and physiology with sleep in health and disorders.

  4. The Transcription Factor Encyclopedia

    PubMed Central

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe. PMID:22458515

  5. Factor Analysis and Counseling Research

    ERIC Educational Resources Information Center

    Weiss, David J.

    1970-01-01

    Topics discussed include factor analysis versus cluster analysis, analysis of Q correlation matrices, ipsativity and factor analysis, and tests for the significance of a correlation matrix prior to application of factor analytic techniques. Techniques for factor extraction discussed include principal components, canonical factor analysis, alpha…

  6. Peptide growth factors, part A

    SciTech Connect

    Barnes, D.; Sirbasku, D.A.

    1987-01-01

    This book contains information on the following topics: Epidermal Growth Factor;Transforming Growth Factors;Bone and Cartilage Growth Factors;Somatomedin/Insulin-Like Growth Factors;Techniques for the Study of Growth Factor Activity;Assays, Phosphorylation, and Surface Membrane Effects.

  7. USAR Recruiting Success Factors.

    DTIC Science & Technology

    1987-12-01

    recruiters. Conventional multi. * variate statistical techniques have not prov ed-adequate in identifying successful recruiters, largely because of the...statistical techniques to the problem of identifying the relative importance of factors affecting recruiter success. Me t hod This study applies a...recruiters; background characteristics, suggestions about recruiter training, the value of various prospecting and selling techniques , workload, attitudes

  8. Introduction to human factors

    SciTech Connect

    Winters, J.M.

    1988-03-01

    Some background is given on the field of human factors. The nature of problems with current human/computer interfaces is discussed, some costs are identified, ideal attributes of graceful system interfaces are outlined, and some reasons are indicated why it's not easy to fix the problems. (LEW)

  9. ERYTHROPOIETIC FACTOR PURIFICATION

    DOEpatents

    White, W.F.; Schlueter, R.J.

    1962-05-01

    A method is given for purifying and concentrating the blood plasma erythropoietic factor. Anemic sheep plasma is contacted three times successively with ion exchange resins: an anion exchange resin, a cation exchange resin at a pH of about 5, and a cation exchange resin at a pH of about 6. (AEC)

  10. Assessment of Human Factors

    NASA Technical Reports Server (NTRS)

    Mount, Frances; Foley, Tico

    1999-01-01

    Human Factors Engineering, often referred to as Ergonomics, is a science that applies a detailed understanding of human characteristics, capabilities, and limitations to the design, evaluation, and operation of environments, tools, and systems for work and daily living. Human Factors is the investigation, design, and evaluation of equipment, techniques, procedures, facilities, and human interfaces, and encompasses all aspects of human activity from manual labor to mental processing and leisure time enjoyments. In spaceflight applications, human factors engineering seeks to: (1) ensure that a task can be accomplished, (2) maintain productivity during spaceflight, and (3) ensure the habitability of the pressurized living areas. DSO 904 served as a vehicle for the verification and elucidation of human factors principles and tools in the microgravity environment. Over six flights, twelve topics were investigated. This study documented the strengths and limitations of human operators in a complex, multifaceted, and unique environment. By focusing on the man-machine interface in space flight activities, it was determined which designs allow astronauts to be optimally productive during valuable and costly space flights. Among the most promising areas of inquiry were procedures, tools, habitat, environmental conditions, tasking, work load, flexibility, and individual control over work.

  11. Managing Multiple Risk Factors.

    DTIC Science & Technology

    1998-09-01

    cardiovascular disease among black women can be better controlled through the use of a stress reduction intervention that reduces the sympathetic nervous...All participants will have high normal (130/80) or mild hypertension and at least two additional risk factors for cardiovascular disease (e.g

  12. Affective Factors: Anxiety

    ERIC Educational Resources Information Center

    Tasnimi, Mahshad

    2009-01-01

    Affective factors seem to play a crucial role in success or failure in second language acquisition. Negative attitudes can reduce learners' motivation and harm language learning, while positive attitudes can do the reverse. Discovering students' attitudes about language will help both teacher and student in teaching learning process. Anxiety is…

  13. Nucleon electromagnetic form factors

    SciTech Connect

    Kees de Jager

    2000-01-01

    A review of data on the nucleon electromagnetic form factors in the space-like region is presented. Recent results from experiments using polarized beams and polarized targets or nucleon recoil polarimeters have yielded a significant improvement on the precision of the data obtained with the traditional Rosenbluth separation. Future plans for extended measurements are outlined.

  14. Nucleon Magnetic Form Factors

    SciTech Connect

    Kees de Jager

    2001-12-01

    A review of data on the nucleon electromagnetic form factors in the space-like region is presented. Recent results from experiments using polarized beams and polarized targets or nucleon recoil polarimeters have yielded a significant improvement on the precision of the data obtained with the traditional Rosenbluth separation. Future plans for extended measurements are outlined.

  15. Nucleon Form Factors

    SciTech Connect

    Kees de Jager

    2002-10-01

    A review of data on the nucleon electro-weak form factors in the space-like region is presented. Recent results from experiments using polarized beams and either polarized targets or nucleon recoil polarimeters have yielded a significant improvement on the precision of the electromagnetic data obtained with the traditional Rosenbluth separation. An outlook is presented of planned experiments.

  16. On The Factor Score Controversy

    ERIC Educational Resources Information Center

    Green, Bert F. Jr.

    1976-01-01

    A summary and interpretation of the recent literature on the indeterminancy of factor scores is given in simple terms. A good index of factor score determinancy is the squared multiple correlation of the factor with the observed variables. (Author)

  17. Factorized Diffusion Map Approximation.

    PubMed

    Amizadeh, Saeed; Valizadegan, Hamed; Hauskrecht, Milos

    2012-01-01

    Diffusion maps are among the most powerful Machine Learning tools to analyze and work with complex high-dimensional datasets. Unfortunately, the estimation of these maps from a finite sample is known to suffer from the curse of dimensionality. Motivated by other machine learning models for which the existence of structure in the underlying distribution of data can reduce the complexity of estimation, we study and show how the factorization of the underlying distribution into independent subspaces can help us to estimate diffusion maps more accurately. Building upon this result, we propose and develop an algorithm that can automatically factorize a high dimensional data space in order to minimize the error of estimation of its diffusion map, even in the case when the underlying distribution is not decomposable. Experiments on both the synthetic and real-world datasets demonstrate improved estimation performance of our method over the standard diffusion-map framework.

  18. Factors stimulating bone formation.

    PubMed

    Lind, M; Bünger, C

    2001-10-01

    The aim of this review is to describe major approaches for stimulating bone healing and to review other factors affecting bone healing. Spinal bone fusion after surgery is a demanding process requiring optimal conditions for clinical success. Bone formation and healing can be enhanced through various methods. Experimental studies have revealed an array of stimulative measures. These include biochemical stimulation by use of hormones and growth factors, physical stimulation through mechanical and electromagnetic measures, and bone grafting by use of bone tissue or bone substitutes. Newer biological techniques such as stem cell transplantation and gene therapy can also be used to stimulate bone healing. Apart from bone transplantation, clinical experience with the many stimulation modalities is limited. Possible areas for clinical use of these novel methods are discussed.

  19. Analytic pion form factor

    NASA Astrophysics Data System (ADS)

    Lomon, Earle L.; Pacetti, Simone

    2016-09-01

    The pion electromagnetic form factor and two-pion production in electron-positron collisions are simultaneously fitted by a vector dominance model evolving to perturbative QCD at large momentum transfer. This model was previously successful in simultaneously fitting the nucleon electromagnetic form factors (spacelike region) and the electromagnetic production of nucleon-antinucleon pairs (timelike region). For this pion case dispersion relations are used to produce the analytic connection of the spacelike and timelike regions. The fit to all the data is good, especially for the newer sets of timelike data. The description of high-q2 data, in the timelike region, requires one more meson with ρ quantum numbers than listed in the 2014 Particle Data Group review.

  20. Factorized Diffusion Map Approximation

    PubMed Central

    Amizadeh, Saeed; Valizadegan, Hamed; Hauskrecht, Milos

    2013-01-01

    Diffusion maps are among the most powerful Machine Learning tools to analyze and work with complex high-dimensional datasets. Unfortunately, the estimation of these maps from a finite sample is known to suffer from the curse of dimensionality. Motivated by other machine learning models for which the existence of structure in the underlying distribution of data can reduce the complexity of estimation, we study and show how the factorization of the underlying distribution into independent subspaces can help us to estimate diffusion maps more accurately. Building upon this result, we propose and develop an algorithm that can automatically factorize a high dimensional data space in order to minimize the error of estimation of its diffusion map, even in the case when the underlying distribution is not decomposable. Experiments on both the synthetic and real-world datasets demonstrate improved estimation performance of our method over the standard diffusion-map framework. PMID:25309676

  1. [Streptococcus pyogenes pathogenic factors].

    PubMed

    Bidet, Ph; Bonacorsi, S

    2014-11-01

    The pathogenicity of ß-hemolytic group A streptococcus (GAS) is particularly diverse, ranging from mild infections, such as pharyngitis or impetigo, to potentially debilitating poststreptococcal diseases, and up to severe invasive infections such as necrotizing fasciitis or the dreaded streptococcal toxic shock syndrome. This variety of clinical expressions, often radically different in individuals infected with the same strain, results from a complex interaction between the bacterial virulence factors, the mode of infection and the immune system of the host. Advances in comparative genomics have led to a better understanding of how, following this confrontation, GAS adapts to the immune system's pressure, either peacefully by reducing the expression of certain virulence factors to achieve an asymptomatic carriage, or on the contrary, by overexpressing them disproportionately, resulting in the most severe forms of invasive infection.

  2. Helicopter human factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.

    1988-01-01

    The state-of-the-art helicopter and its pilot are examined using the tools of human-factors analysis. The significant role of human error in helicopter accidents is discussed; the history of human-factors research on helicopters is briefly traced; the typical flight tasks are described; and the noise, vibration, and temperature conditions typical of modern military helicopters are characterized. Also considered are helicopter controls, cockpit instruments and displays, and the impact of cockpit design on pilot workload. Particular attention is given to possible advanced-technology improvements, such as control stabilization and augmentation, FBW and fly-by-light systems, multifunction displays, night-vision goggles, pilot night-vision systems, night-vision displays with superimposed symbols, target acquisition and designation systems, and aural displays. Diagrams, drawings, and photographs are provided.

  3. Human factors workplace considerations

    NASA Technical Reports Server (NTRS)

    Haines, Richard F.

    1988-01-01

    Computer workstations assume many different forms and play different functions today. In order for them to assume the effective interface role which they should play they must be properly designed to take into account the ubiguitous human factor. In addition, the entire workplace in which they are used should be properly configured so as to enhance the operational features of the individual workstation where possible. A number of general human factors workplace considerations are presented. This ongoing series of notes covers such topics as achieving comfort and good screen visibility, hardware issues (e.g., mouse maintenance), screen symbology features (e.g., labels, cursors, prompts), and various miscellaneous subjects. These notes are presented here in order to: (1) illustrate how one's workstation can be used to support telescience activities of many other people working within an organization, and (2) provide a single complete set of considerations for future reference.

  4. Factors regulating microglia activation

    PubMed Central

    Kierdorf, Katrin; Prinz, Marco

    2013-01-01

    Microglia are resident macrophages of the central nervous system (CNS) that display high functional similarities to other tissue macrophages. However, it is especially important to create and maintain an intact tissue homeostasis to support the neuronal cells, which are very sensitive even to minor changes in their environment. The transition from the “resting” but surveying microglial phenotype to an activated stage is tightly regulated by several intrinsic (e.g., Runx-1, Irf8, and Pu.1) and extrinsic factors (e.g., CD200, CX3CR1, and TREM2). Under physiological conditions, minor changes of those factors are sufficient to cause fatal dysregulation of microglial cell homeostasis and result in severe CNS pathologies. In this review, we discuss recent achievements that gave new insights into mechanisms that ensure microglia quiescence. PMID:23630462

  5. FACTORS INFLUENCING THE DESIGN OF BIOACCUMULATION FACTOR AND BIOTA-SEDIMENT ACCUMULATION FACTOR FIELD STUDIES

    EPA Science Inventory

    General guidance for designing field studies to measure bioaccumulation factors (BAFs) and biota-sediment accumulation factors (BSAFs) is not available. To develop such guidance, a series of modeling simulations were performed to evaluate the underlying factors and principles th...

  6. FACTORS INFLUENCING THE DESIGN OF BIOACCUMULATION FACTOR AND BIOTA-SEDIMENT ACCUMULATION FACTOR FIELD STUDIES

    EPA Science Inventory

    A series of modeling simulations were performed to develop an understanding of the underlying factors and principles involved in developing field sampling designs for measuring bioaccumulation factors (BAFs) and biota-sediment accumulation factors (BSAFs. These simulations reveal...

  7. Psychosomatic factors in dermatology.

    PubMed

    Urpe, Mauro; Pallanti, Stefano; Lotti, Torello

    2005-10-01

    Psychosomatics describes any aspect of dermatology with psychologic or psychiatric elements. Dermatologists know that a significant proportion of their practice involves patients for whom psychologic elements either partially or sometimes entirely dominate their presenting chief complaints. This article explores the role of psychosomatic factors in dermatologic disorders. The authors discuss the clinical interface between psychiatry, psychology and dermatology and the interpretation of possible relationships between cutaneous diseases, the role of the mind, and psychotherapeutic interventions.

  8. The malingering factor.

    PubMed

    Williams, J Michael

    2011-04-01

    The influence of malingering and suboptimal performance on neuropsychological tests has become a major interest of clinical neuropsychologists. Methods to detect malingering have focused on specialized tests or embedded patterns associated with malingering present in the conventional neuropsychology tests. There are two stages to the study of their validity. The first stage involves whether the method can discriminate malingering subjects from those who are not malingering. In the second stage, they must be examined for their relationship to the conventional tests used to establish impairment and disability. Constantinou, Bauer, Ashendorf, Fisher, and McCaffrey (2005. Is poor performance on recognition memory effort measures indicative of generalized poor performance on neuropsychological tests? Archives of Clinical Neuropsychology, 20, 191-198.) conducted the only study in which correlations are presented between a commonly used symptom validity test, the Test of Memory Malingering (TOMM) and the subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). A factor analysis was conducted using these correlations. It revealed a clear malingering factor that explained significant variance in the TOMM and the WAIS-R subtests. The relationship of malingering with cognitive tests is complex: some tests are sensitive to malingering and others are not. Factor analysis can summarize the magnitude of variance associated with each test and reveal the patterns of inter-relationships between malingering and clinical tests. The analysis also suggested that malingering assessment methods could be improved by the addition of timing the responses.

  9. Molecular factors in migraine

    PubMed Central

    Kowalska, Marta; Prendecki, Michał; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2016-01-01

    Migraine is a common neurological disorder that affects 11% of adults worldwide. This disease most likely has a neurovascular origin. Migraine with aura (MA) and more common form - migraine without aura (MO) – are the two main clinical subtypes of disease. The exact pathomechanism of migraine is still unknown, but it is thought that both genetic and environmental factors are involved in this pathological process. The first genetic studies of migraine were focused on the rare subtype of MA: familial hemiplegic migraine (FHM). The genes analysed in familial and sporadic migraine are: MTHFR, KCNK18, HCRTR1, SLC6A4, STX1A, GRIA1 and GRIA3. It is possible that migraine is a multifactorial disease with polygenic influence. Recent studies have shown that the pathomechanisms of migraine involves both factors responsible for immune response and oxidative stress such as: cytokines, tyrosine metabolism, homocysteine; and factors associated with pain transmission and emotions e.g.: serotonin, hypocretin-1, calcitonin gene-related peptide, glutamate. The correlations between genetic variants of the HCRTR1 gene, the polymorphism 5-HTTLPR and hypocretin-1, and serotonin were observed. It is known that serotonin inhibits the activity of hypocretin neurons and may affect the appearance of the aura during migraine attack. The understanding of the molecular mechanisms of migraine, including genotype-phenotype correlations, may contribute to finding markers important for the diagnosis and treatment of this disease. PMID:27191890

  10. Human Factors Review Plan

    SciTech Connect

    Paramore, B.; Peterson, L.R.

    1985-12-01

    ''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management.

  11. Fano factor estimation.

    PubMed

    Rajdl, Kamil; Lansky, Petr

    2014-02-01

    Fano factor is one of the most widely used measures of variability of spike trains. Its standard estimator is the ratio of sample variance to sample mean of spike counts observed in a time window and the quality of the estimator strongly depends on the length of the window. We investigate this dependence under the assumption that the spike train behaves as an equilibrium renewal process. It is shown what characteristics of the spike train have large effect on the estimator bias. Namely, the effect of refractory period is analytically evaluated. Next, we create an approximate asymptotic formula for the mean square error of the estimator, which can also be used to find minimum of the error in estimation from single spike trains. The accuracy of the Fano factor estimator is compared with the accuracy of the estimator based on the squared coefficient of variation. All the results are illustrated for spike trains with gamma and inverse Gaussian probability distributions of interspike intervals. Finally, we discuss possibilities of how to select a suitable observation window for the Fano factor estimation.

  12. Nucleon Electromagnetic Form Factors

    SciTech Connect

    Kees de Jager

    2004-08-01

    Although nucleons account for nearly all the visible mass in the universe, they have a complicated structure that is still incompletely understood. The first indication that nucleons have an internal structure, was the measurement of the proton magnetic moment by Frisch and Stern (1933) which revealed a large deviation from the value expected for a point-like Dirac particle. The investigation of the spatial structure of the nucleon, resulting in the first quantitative measurement of the proton charge radius, was initiated by the HEPL (Stanford) experiments in the 1950s, for which Hofstadter was awarded the 1961 Nobel prize. The first indication of a non-zero neutron charge distribution was obtained by scattering thermal neutrons off atomic electrons. The recent revival of its experimental study through the operational implementation of novel instrumentation has instigated a strong theoretical interest. Nucleon electro-magnetic form factors (EMFFs) are optimally studied through the exchange of a virtual photon, in elastic electron-nucleon scattering. The momentum transferred to the nucleon by the virtual photon can be selected to probe different scales of the nucleon, from integral properties such as the charge radius to scaling properties of its internal constituents. Polarization instrumentation, polarized beams and targets, and the measurement of the polarization of the recoiling nucleon have been essential in the accurate separation of the charge and magnetic form factors and in studies of the elusive neutron charge form factor.

  13. Nucleon form factors '99

    SciTech Connect

    Kees de Jager; B. Pire

    1999-06-01

    The authors review recent progress in the experimental knowledge of and theoretical speculations about nucleon form factors, with special emphasis on the large Q{sup 2} region. There is now a long history of continuous progress in the understanding of electromagnetic form factors at large momentum transfer. After the pioneering works leading to the celebrated quark counting rules, the understanding of hard scattering exclusive processes has been solidly founded. A perturbative QCD subprocess is factorized from a wave function-like distribution amplitude {var_phi}(x{sub i},Q{sup 2}) (x{sub i} being the light cone fractions of momentum carried by valence quarks), the Q{sup 2} dependence of which is analyzed in the renormalization group approach. Although an asymptotic expression emerges from this analysis for the x dependence of the distribution, it was quickly understood that the evolution to the asymptotic Q{sub 2} is very slow and that indeed some non perturbative input is required to get reliable estimates of this distribution amplitude at measurable Q{sup 2}.

  14. The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFβ1 responses in human proximal-tubule epithelial cells

    PubMed Central

    Phanish, Mysore K.; Wahab, Nadia A.; Colville-Nash, Paul; Hendry, Bruce M.; Dockrell, Mark E. C.

    2005-01-01

    In chronic renal diseases, progressive loss of renal function correlates with advancing tubulo-interstitial fibrosis. TGFβ1-Smad (transforming growth factor-β1–Sma and Mad protein) signalling plays an important role in the development of renal tubulo-interstitial fibrosis. Secretion of CTGF (connective-tissue growth factor; CCN2) by PTECs (proximal-tubule epithelial cells) and EMT (epithelial–mesenchymal transdifferentiation) of PTECs to myofibroblasts in response to TGFβ are critical Smad-dependent events in the development of tubulo-interstitial fibrosis. In the present study we have investigated the distinct contributions of Smad2 and Smad3 to expression of CTGF, E-cadherin, α-SMA (α-smooth-muscle actin) and MMP-2 (matrix-metalloproteinase-2) in response to TGFβ1 treatment in an in vitro culture model of HKC-8 (transformed human PTECs). RNA interference was used to achieve selective and specific knockdown of Smad2 and Smad3. Cellular E-cadherin, α-SMA as well as secreted CTGF and MMP-2 were assessed by Western immunoblotting. TGFβ1 treatment induced a fibrotic phenotype with increased expression of CTGF, MMP-2 and α-SMA, and decreased expression of E-cadherin. TGFβ1-induced increases in CTGF and decreases in E-cadherin expression were Smad3-dependent, whereas increases in MMP-2 expression were Smad2-dependent. Increases in α-SMA expression were dependent on both Smad2 and Smad3 and were abolished by combined knockdown of both Smad2 and Smad3. In conclusion, we have demonstrated distinct roles for Smad2 and Smad3 in TGFβ1-induced CTGF expression and markers of EMT in human PTECs. This can be of therapeutic value in designing targeted anti-fibrotic therapies for tubulo-interstitial fibrosis. PMID:16253118

  15. Risk Factors for Eating Disorders

    ERIC Educational Resources Information Center

    Striegel-Moore, Ruth H.; Bulik, Cynthia M.

    2007-01-01

    The authors review research on risk factors for eating disorders, restricting their focus to studies in which clear precedence of the hypothesized risk factor over onset of the disorder is established. They illustrate how studies of sociocultural risk factors and biological factors have progressed on parallel tracks and propose that major advances…

  16. Inhibition of the activation of Hageman factor (factor XII) by platelet factor 4.

    PubMed

    Dumenco, L L; Everson, B; Culp, L A; Ratnoff, O D

    1988-09-01

    Platelet factor 4 is a polypeptide constituent of platelet alpha granules that is released during platelet aggregation and inhibits heparin-mediated reactions. Hageman factor (factor XII) is a plasma proenzyme that, when activated by certain negatively charged agents, initiates clotting via the intrinsic pathway of thrombin formation. In earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by dextran sulfate or cerebrosides, but not activation of Hageman factor by kaolin or ellagic acid. In the present study we examined the mechanisms of inhibition by platelet factor 4, using purified reagents. Platelet factor 4 inhibited activation of Hageman factor by ellagic acid, as measured by amidolysis of a synthetic substrate of activated Hageman factor, an effect inhibited by heparin or by an anti-platelet factor 4 antiserum. Coating glass tubes with platelet factor 4 before addition of normal plasma significantly lengthened the partial thromboplastin time of normal plasma. In addition, the clot-promoting properties of kaolin were inhibited by its prior exposure to platelet factor 4. Thus, the inhibitory properties of platelet factor 4 directed against the activation of Hageman factor were confirmed in a purified system. In this purified system, in contrast to earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by glass, ellagic acid, or kaolin.

  17. From compatible factorization to near-compatible factorization

    NASA Astrophysics Data System (ADS)

    Aldiabat, Raja'i.; Ibrahim, Haslinda

    2014-12-01

    A compatible factorization of order ν, is an ν× ν-1/2 array in which the entries in row i form a near-one-factor with focus i, and the triples associated with the rows contain no repetitions. In this paper, we aim to amend this compatible factorization so that we can display ν(ν-1)/2 - 2ν/3 triples with the minimum repeated triples. Throughout this paper we propose a new type of factorization called near-compatible factorization. First, we present the compatible factorization towards developing a near-compatible factorization. Second, we discuss briefly the necessary and sufficient conditions for the existence of near-compatible factorization. Then, we exemplify the construction for case ν = 9 as a groundwork in developing near-compatible factorization.

  18. Neutron quality factor

    SciTech Connect

    1995-06-01

    Both the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP) have recommended that the radiation quality weighting factor for neutrons (Q{sub n}, or the corresponding new modifying factor, w{sub R}) be increased by a value of two for most radiation protection practices. This means an increase in the recommended value for Q{sub n} from a nominal value of 10 to a nominal value of 20. This increase may be interpreted to mean that the biological effectiveness of neutrons is two times greater than previously thought. A decision to increase the value of Q{sub n} will have a major impact on the regulations and radiation protection programs of Federal agencies responsible for the protection of radiation workers. Therefore, the purposes of this report are: (1) to examine the general concept of {open_quotes}quality factor{close_quotes} (Q) in radiation protection and the rationale for the selection of specific values of Q{sub n}; and (2) to make such recommendations to the Federal agencies, as appropriate. This report is not intended to be an exhaustive review of the scientific literature on the biological effects of neutrons, with the aim of defending a particular value for Q{sub n}. Rather, the working group examined the technical issues surrounding the current recommendations of scientific advisory bodies on this matter, with the aim of determining if these recommendations should be adopted by the Federal agencies. Ultimately, the group concluded that there was no compelling basis for a change in Q{sub n}. The report was prepared by Federal scientists working under the auspices of the Science Panel of the Committee on Interagency Radiation Research and Policy Coordination (CIRRPC).

  19. Milestones and Impact Factors

    PubMed Central

    2010-01-01

    Environmental Health has just received its first Impact Factor by Thomson ISI. At a level of 2.48, this achievement is quite satisfactory and places Environmental Health in the top 25% of environmental science journals. When the journal was launched in 2002, it was still unclear whether the Open Access publishing model could be made into a viable commercial enterprise within the biomedical field. During the past eight years, Open Access journals have become widely available, although still covering only about 15% of journal titles. Major funding agencies and institutions, including prominent US universities, now require that researchers publish in Open Access journals. Because of the profound role of scientific journals for the sharing of results and communication between researchers, the advent of Open Access may be of as much significance as the transition from handwriting to printing via moveable type. As Environmental Health is an electronic Open Access journal, the numbers of downloads at the journal website can be retrieved. The top-20 list of articles most frequently accessed shows that all of them have been downloaded over 10,000 times. Back in 2002, the first article published was accessed only 49 times during the following month. A year later, the server had over 1,000 downloads per month, and now the total number of monthly downloads approaches 50,000. These statistics complement the Impact Factor and confirm the viability of Open Access in our field of research. The advent of digital media and its decentralized mode of distribution - the internet - have dramatically changed the control and financing of scientific information dissemination, while facilitating peer review, accelerating editorial handling, and supporting much needed transparency. Both the meaning and means of "having an impact" are therefore changing, as will the degree and way in which scientific journals remain "factors" in that impact. PMID:20615249

  20. Human Factors Model

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Jack is an advanced human factors software package that provides a three dimensional model for predicting how a human will interact with a given system or environment. It can be used for a broad range of computer-aided design applications. Jack was developed by the computer Graphics Research Laboratory of the University of Pennsylvania with assistance from NASA's Johnson Space Center, Ames Research Center and the Army. It is the University's first commercial product. Jack is still used for academic purposes at the University of Pennsylvania. Commercial rights were given to Transom Technologies, Inc.

  1. The "impact factor" revisited

    PubMed Central

    Dong, Peng; Loh, Marie; Mondry, Adrian

    2005-01-01

    The number of scientific journals has become so large that individuals, institutions and institutional libraries cannot completely store their physical content. In order to prioritize the choice of quality information sources, librarians and scientists are in need of reliable decision aids. The "impact factor" (IF) is the most commonly used assessment aid for deciding which journals should receive a scholarly submission or attention from research readership. It is also an often misunderstood tool. This narrative review explains how the IF is calculated, how bias is introduced into the calculation, which questions the IF can or cannot answer, and how different professional groups can benefit from IF use. PMID:16324222

  2. Electromagnetic pion form factor

    SciTech Connect

    Roberts, C.D.

    1995-08-01

    A phenomenological Dyson-Schwinger/Bethe-Salpeter equation approach to QCD, formalized in terms of a QCD-based model field theory, the Global Color-symmetry Model (GCM), was used to calculate the generalized impulse approximation contribution to the electromagnetic pion form factor at space-like q{sup 2} on the domain [0,10] GeV{sup 2}. In effective field theories this form factor is sometimes understood as simply being due to Vector Meson Dominance (VMD) but this does not allow for a simple connection with QCD where the VMD contribution is of higher order than that of the quark core. In the GCM the pion is treated as a composite bound state of a confined quark and antiquark interacting via the exchange of colored vector-bosons. A direct study of the quark core contribution is made, using a quark propagator that manifests the large space-like-q{sup 2} properties of QCD, parameterizes the infrared behavior and incorporates confinement. It is shown that the few parameters which characterize the infrared form of the quark propagator may be chosen so as to yield excellent agreement with the available data. In doing this one directly relates experimental observables to properties of QCD at small space-like-q{sup 2}. The incorporation of confinement eliminates endpoint and pinch singularities in the calculation of F{sub {pi}}(q{sup 2}). With asymptotic freedom manifest in the dressed quark propagator the calculation yields q{sup 4}F{sub {pi}}(q{sup 2}) = constant, up to [q{sup 2}]- corrections, for space-like-q{sup 2} {approx_gt} 35 GeV{sup 2}, which indicates that soft, nonperturbative contributions dominate the form factor at presently accessible q{sup 2}. This means that the often-used factorization Ansatz fails in this exclusive process. A paper describing this work was submitted for publication. In addition, these results formed the basis for an invited presentation at a workshop on chiral dynamics and will be published in the proceedings.

  3. SARSCEST (human factors)

    NASA Technical Reports Server (NTRS)

    Parsons, H. Mcilvaine

    1988-01-01

    People interact with the processes and products of contemporary technology. Individuals are affected by these in various ways and individuals shape them. Such interactions come under the label 'human factors'. To expand the understanding of those to whom the term is relatively unfamiliar, its domain includes both an applied science and applications of knowledge. It means both research and development, with implications of research both for basic science and for development. It encompasses not only design and testing but also training and personnel requirements, even though some unwisely try to split these apart both by name and institutionally. The territory includes more than performance at work, though concentration on that aspect, epitomized in the derivation of the term ergonomics, has overshadowed human factors interest in interactions between technology and the home, health, safety, consumers, children and later life, the handicapped, sports and recreation education, and travel. Two aspects of technology considered most significant for work performance, systems and automation, and several approaches to these, are discussed.

  4. [Fibroblast growth factor-2].

    PubMed

    Faitová, J

    2004-01-01

    Fibroblast growth factor-2 is a member of a large family of proteins that bind heparin and heparan sulfate and modulate the function of a wide range of cell types. FGF-2 occurs in several isoforms resulting from alternative initiations of traslation: an 18 kDa cytoplasmic isoform and four larger molecular weight nuclear isoforms (22, 22.5, 24 and 34 kDa). It acts mainly through a paracrine/autocrine mechanism involving high affinity transmembrane receptors and heparan sulfate proteoglycan low affinity receptors. It is expressed mostly in tissues of mesoderm and neuroectoderm origin, and plays an important role in mesoderm induction, stimulates the growth and development of the new blood vessels (angiogenesis), normal wound healing and tissue development. FGF-2 positively regulates hematopoiesis by acting on various cellular targets: stromal cells, early and committed hematopoietic progenitors and possibly some mature blood cells. FGF-2 is a potent hematopoietic growth factor that is likely to play an important role in physiological and pathological hematopoiesis.

  5. Fungal CSL transcription factors

    PubMed Central

    Převorovský, Martin; Půta, František; Folk, Petr

    2007-01-01

    Background The CSL (CBF1/RBP-Jκ/Suppressor of Hairless/LAG-1) transcription factor family members are well-known components of the transmembrane receptor Notch signaling pathway, which plays a critical role in metazoan development. They function as context-dependent activators or repressors of transcription of their responsive genes, the promoters of which harbor the GTG(G/A)GAA consensus elements. Recently, several studies described Notch-independent activities of the CSL proteins. Results We have identified putative CSL genes in several fungal species, showing that this family is not confined to metazoans. We have analyzed their sequence conservation and identified the presence of well-defined domains typical of genuine CSL proteins. Furthermore, we have shown that the candidate fungal protein sequences contain highly conserved regions known to be required for sequence-specific DNA binding in their metazoan counterparts. The phylogenetic analysis of the newly identified fungal CSL proteins revealed the existence of two distinct classes, both of which are present in all the species studied. Conclusion Our findings support the evolutionary origin of the CSL transcription factor family in the last common ancestor of fungi and metazoans. We hypothesize that the ancestral CSL function involved DNA binding and Notch-independent regulation of transcription and that this function may still be shared, to a certain degree, by the present CSL family members from both fungi and metazoans. PMID:17629904

  6. Leukemia Inhibitory Factor (LIF)

    PubMed Central

    Nicola, Nicos A; Babon, Jeffrey J

    2015-01-01

    Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. It utilises a receptor that consists of the LIF receptor β and gp130 and this receptor complex is also used by ciliary neurotrophic growth factor (CNTF), oncostatin M, cardiotrophin1 (CT1) and cardiotrophin-like cytokine (CLC). Despite common signal transduction mechanisms (JAK/STAT, MAPK and PI3K) LIF can have paradoxically opposite effects in different cell types including stimulating or inhibiting each of cell proliferation, differentiation and survival. While LIF can act on a wide range of cell types, LIF knockout mice have revealed that many of these actions are not apparent during ordinary development and that they may be the result of induced LIF expression during tissue damage or injury. Nevertheless LIF does appear to have non-redundant actions in maternal receptivity to blastocyst implantation, placental formation and in the development of the nervous system. LIF has also found practical use in the maintenance of self-renewal and totipotency of embryonic stem cells and induced pluripotent stem cells. PMID:26187859

  7. The atrial natriuretic factor.

    PubMed Central

    Genest, J

    1986-01-01

    In less than three years since the rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats was reported the factor responsible for the diuretic, natriuretic, and vasodilating activity of the atrial homogenates was isolated, its chemical structure elucidated, and its total synthesis achieved. Also the cDNA and the gene encoding for the atrial natriuretic factor in mice, rats, and man have been cloned and the chromosomal site identified. The major effects of this hormone are vasodilatation, prevention and inhibition of the contraction induced by noradrenaline and angiotensin II, diuresis, and natriuresis associated in most instances with a pronounced increase in glomerular filtration rate and filtration fraction, inhibition of aldosterone secretion, and considerable stimulation of particulate guanylate cyclase activity. High density specific binding sites have been demonstrated in the zona glomerulosa of the adrenal cortex, in the renal glomeruli, and in the collecting ducts, and in the brain areas involved in the regulation of blood pressure and of sodium and water (AV3V region, subfornical organ, nucleus tractus solitarius, area postrema). Images Fig 1 Fig 5 PMID:2945572

  8. Auxin response factors.

    PubMed

    Chandler, John William

    2016-05-01

    Auxin signalling involves the activation or repression of gene expression by a class of auxin response factor (ARF) proteins that bind to auxin response elements in auxin-responsive gene promoters. The release of ARF repression in the presence of auxin by the degradation of their cognate auxin/indole-3-acetic acid repressors forms a paradigm of transcriptional response to auxin. However, this mechanism only applies to activating ARFs, and further layers of complexity of ARF function and regulation are being revealed, which partly reflect their highly modular domain structure. This review summarizes our knowledge concerning ARF binding site specificity, homodimer and heterodimer multimeric ARF association and cooperative function and how activator ARFs activate target genes via chromatin remodelling and evolutionary information derived from phylogenetic comparisons from ARFs from diverse species. ARFs are regulated in diverse ways, and their importance in non-auxin-regulated pathways is becoming evident. They are also embedded within higher-order transcription factor complexes that integrate signalling pathways from other hormones and in response to the environment. The ways in which new information concerning ARFs on many levels is causing a revision of existing paradigms of auxin response are discussed.

  9. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    SciTech Connect

    Gan, Lu; Xue, Jian-Xin; Li, Xin; Liu, De-Song; Ge, Yan; Ni, Pei-Yan; Deng, Lin; Lu, You; Jiang, Wei

    2011-05-27

    Highlights: {yields} Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. {yields} Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. {yields} VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. {yields} LPA-LPAR1/3 signaling regulated TGF{beta}1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. {yields} LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGF{beta}1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor {beta}1 (TGF{beta}1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1

  10. Pediatric rhinitis risk factors

    PubMed Central

    Ji, Yaofeng; Liu, Yin; Yang, Na

    2016-01-01

    Rhinitis is a common global disorder that impacts on the quality of life of the sufferer and caregivers. Treatment for pediatric rhinitis is empirical and does not include a detailed history of the allergy triggers or allergy testing. Thus, allergen avoidance advice is not tailored to the child's sensitivities, which may result in adenoid hypertrophy. However, infant onset rhinitis, especially its relationship with respiratory viruses, remains to be further clarified. Rhinitis basically involves inflammation of the upper nasal lining, presenting typically with symptoms of runny nose (rhinorrhea), nasal blockage, and/or sneezing. While not typically fatal, it does impose significant health, psychological, and monetary burden to its sufferers, and is thus considered a global health problem. Previous findings showed that immunotherapy had significant clinical efficacy in children with allergic rhinitis. The present review article aims to highlight recent perspectives pertaining to the rhinitis risk factors especially in pediatric patients. PMID:27698737

  11. Pion form factor

    SciTech Connect

    Ryong Ji, C.; Pang, A.; Szczepaniak, A.

    1994-04-01

    It is pointed out that the correct criterion to define the legal PQCD contribution to the exclusive processes in the lightcone perturbative expansion should be based on the large off-shellness of the lightcone energy in the intermediate states. In the lightcone perturbative QCD calculation of the pion form factor, the authors find that the legal PQCD contribution defined by the lightcone energy cut saturates in the smaller Q{sup 2} region compared to that defined by the gluon four-momentum square cut. This is due to the contribution by the highly off-energy-shell gluons in the end point regions of the phase space, indicating that the gluon four-momentum-square cut may have cut too much to define the legal PQCD.

  12. Unity power factor converter

    NASA Technical Reports Server (NTRS)

    Wester, Gene W. (Inventor)

    1980-01-01

    A unity power factor converter capable of effecting either inversion (dc-to-dc) or rectification (ac-to-dc), and capable of providing bilateral power control from a DC source (or load) through an AC transmission line to a DC load (or source) for power flow in either direction, is comprised of comparators for comparing the AC current i with an AC signal i.sub.ref (or its phase inversion) derived from the AC ports to generate control signals to operate a switch control circuit for high speed switching to shape the AC current waveform to a sine waveform, and synchronize it in phase and frequency with the AC voltage at the AC ports, by selectively switching the connections to a series inductor as required to increase or decrease the current i.

  13. [Pathogenic factors of mycoplasma].

    PubMed

    Shimizu, Takashi

    2015-01-01

    Mycoplasmas are smallest organisms capable of self-replication and cause various diseases in human. Especially, Mycoplasma pneumoniae is known as an etiological agent of pneumonia. From 2010 to 2012, epidemics of M. pneumoniae infections were reported worldwide (e.g., in France, Israel, and Japan). In the diseases caused by mycoplasmas, strong inflammatory responses induced by mycoplasmas have been thought to be important. However, mycoplasmas lack of cell wall and do not possess inflammation-inducing endotoxin such as lipopolysaccharide (LPS). We purified inflammation-inducing factors from pathogenic mycoplasmas and identified that they were lipoproteins. Lipoproteins derived from mycoplasmas induced inflammatory responses through Toll-like receptor (TLR) 2. In addition, we demonstrated that cytadherent property of M. pneumoniae played an important role in induction of inflammatory responses. Cytadherent property of M. pneumoniae induced inflammatory responses through TLR2 independent pathway. TLR4, inflammasomes, and autophagy were involved in this TLR2 independent induction of inflammatory responses.

  14. Nucleon Electromagnetic Form Factors

    SciTech Connect

    Marc Vanderhaeghen; Charles Perdrisat; Vina Punjabi

    2007-10-01

    There has been much activity in the measurement of the elastic electromagnetic proton and neutron form factors in the last decade, and the quality of the data has greatly improved by performing double polarization experiments, in comparison with previous unpolarized data. Here we review the experimental data base in view of the new results for the proton, and neutron, obtained at JLab, MAMI, and MIT-Bates. The rapid evolution of phenomenological models triggered by these high-precision experiments will be discussed, including the recent progress in the determination of the valence quark generalized parton distributions of the nucleon, as well as the steady rate of improvements made in the lattice QCD calculations.

  15. Exposure factors handbook

    SciTech Connect

    Konz, J.J.; Lisi, K.; Friebele, E.; Dixon, D.A.

    1989-07-01

    The document provides a summary of the available data on various factors used in assessing human exposure including drinking-water consumption, consumption rates of broad classes of food including fruits, vegetables, beef, dairy products, and fish; soil ingestion; inhalation rate; skin area; lifetime; activity patterns; and body weight. Additionally, a number of specific exposure scenarios are identified with recommendations for default values to use when site-specific data are not available. The basic equations using these parameters to calculate exposure levels are also presented for each scenario. Default values are presented as ranges from typical to reasonable worst case and as frequency distributions where appropriate data were available. Finally, procedures for assessing the uncertainties in exposure assessments are also presented with illustrative examples. These procedures include qualitative and quantitative methods such as Monte Carlo and sensitivity analysis.

  16. Tumor necrosis factor.

    PubMed

    Chu, Wen-Ming

    2013-01-28

    Tumor necrosis factor (TNF) is a critical cytokine, which contributes to both physiological and pathological processes. This mini-review will briefly touch the history of TNF discovery, its family members and its biological and pathological functions. Then, it will focus on new findings on the molecular mechanisms of how TNF triggers activation of the NF-κB and AP-1 pathways, which are critical for expression of pro-inflammatory cytokines, as well as the MLKL cascade, which is critical for the generation of ROS in response to TNF. Finally, this review will briefly summarize recent advances in understanding TNF-induced cell survival, apoptosis and necrosis (also called necroptosis). Understanding new findings and emerging concepts will impact future research on the molecular mechanisms of TNF signaling in immune disorders and cancer-related inflammation.

  17. Psychosomatic factors in pruritus.

    PubMed

    Tey, Hong Liang; Wallengren, Joanna; Yosipovitch, Gil

    2013-01-01

    Pruritus and psyche are intricately and reciprocally related, with psychophysiological evidence and psychopathological explanations helping us to understand their complex association. Their interaction may be conceptualized and classified into 3 groups: pruritic diseases with psychiatric sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Management of chronic pruritus is directed at treating the underlying causes and adopting a multidisciplinary approach to address the dermatologic, somatosensory, cognitive, and emotional aspects. Pharmcotherapeutic agents that are useful for chronic pruritus with comorbid depression and/or anxiety comprise selective serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants (amitriptyline and doxepin), and anticonvulsants (gabapentin, pregabalin); the role of neurokinin receptor-1 antagonists awaits verification. Antipsychotics are required for treating itch and formication associated with schizophrenia and delusion of parasitosis (including Morgellons disease).

  18. Psychosomatic factors in pruritus

    PubMed Central

    Tey, Hong Liang; Wallengren, Joanna; Yosipovitch, Gil

    2013-01-01

    Pruritus and psyche are intricately and reciprocally related, with psychophysiological evidence and psychopathological explanations helping us to understand their complex association. Their interaction may be conceptualized and classified into 3 groups: pruritic diseases with psychiatric sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Management of chronic pruritus is directed at treating the underlying causes and adopting a multidisciplinary approach to address the dermatologic, somatosensory, cognitive, and emotional aspects. Pharmcotherapeutic agents that are useful for chronic pruritus with comorbid depression and/or anxiety comprise selective serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants (amitriptyline and doxepin), and anticonvulsants (gabapentin, pregabalin); the role of neurokinin receptor-1 antagonists awaits verification. Antipsychotics are required for treating itch and formication associated with schizophrenia and delusion of parasitosis (including Morgellons disease). PMID:23245971

  19. Factor Rotation and Standard Errors in Exploratory Factor Analysis

    ERIC Educational Resources Information Center

    Zhang, Guangjian; Preacher, Kristopher J.

    2015-01-01

    In this article, we report a surprising phenomenon: Oblique CF-varimax and oblique CF-quartimax rotation produced similar point estimates for rotated factor loadings and factor correlations but different standard error estimates in an empirical example. Influences of factor rotation on asymptotic standard errors are investigated using a numerical…

  20. Helicopter Human Factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.; Sridhar, Banavar (Technical Monitor)

    1995-01-01

    Even under optimal conditions, helicopter flight is a most demanding form of human-machine interaction, imposing continuous manual, visual, communications, and mental demands on pilots. It is made even more challenging by small margins for error created by the close proximity of terrain in NOE flight and missions flown at night and in low visibility. Although technology advances have satisfied some current and proposed requirements, hardware solutions alone are not sufficient to ensure acceptable system performance and pilot workload. However, human factors data needed to improve the design and use of helicopters lag behind advances in sensor, display, and control technology. Thus, it is difficult for designers to consider human capabilities and limitations when making design decisions. This results in costly accidents, design mistakes, unrealistic mission requirements, excessive training costs, and challenge human adaptability. NASA, in collaboration with DOD, industry, and academia, has initiated a program of research to develop scientific data bases and design principles to improve the pilot/vehicle interface, optimize training time and cost, and maintain pilot workload and system performance at an acceptable level. Work performed at Ames, and by other research laboratories, will be reviewed to summarize the most critical helicopter human factors problems and the results of research that has been performed to: (1) Quantify/model pilots use of visual cues for vehicle control; (2) Improve pilots' performance with helmet displays of thermal imagery and night vision goggles for situation awareness and vehicle control; (3) Model the processes by which pilots encode maps and compare them to the visual scene to develop perceptually and cognitively compatible electronic map formats; (4) Evaluate the use of spatially localized auditory displays for geographical orientation, target localization, radio frequency separation; (5) Develop and flight test control

  1. Air Emissions Factors and Quantification

    EPA Pesticide Factsheets

    Emissions factors are used in developing air emissions inventories for air quality management decisions and in developing emissions control strategies. This area provides technical information on and support for the use of emissions factors.

  2. FACTORING TO FIT OFF DIAGONALS.

    DTIC Science & Technology

    imply an upper bound on the number of factors. When applied to somatotype data, the method improved substantially on centroid solutions and indicated a reinterpretation of earlier factoring studies. (Author)

  3. Environmental factors and aggressive behavior

    SciTech Connect

    Anderson, A.C.

    1982-07-01

    This paper briefly reviews some of the research areas which indicate a correlation between environmental factors and initiation of aggressive behavior. Environmental factors including lunar influences, month of birth, climate and the effects of crowding and certain chemicals are discussed.

  4. Current status on tissue factor activation of factor VIIa.

    PubMed

    Persson, Egon; Olsen, Ole H

    2010-04-01

    Free factor VIIa displays a zymogen-like behavior with low intrinsic activity. Formation of a complex between factor VIIa and tissue factor is necessary to enhance the procoagulant activity of factor VIIa, not only by providing membrane localization, substrate exosites and positioning the active site at an appropriate distance above the surface but also by allosteric enhancement of the enzymatic activity, and this event signals initiation of blood coagulation. The interaction is of high affinity and all the domains are engaged at the interface. The crosstalk between the protease domain of factor VIIa, in particular residue Met-306, and the N-terminal domain of tissue factor provides the starting point for the allosteric activation of factor VIIa. The pathway(s) of conformational transitions in factor VIIa ensuing tissue factor binding has not been entirely mapped. The present paper is a brief compilation of our current knowledge of the allosteric mechanism by which tissue factor induces and stabilizes the active conformation of factor VIIa.

  5. THE ASSAY AND PROPERTIES OF LABILE FACTOR (FACTOR V)

    PubMed Central

    Quick, Armand J.

    1960-01-01

    Human oxalated plasma stored at 4° C. until the prothrombin time is increased beyond 60 sec. is a reliable medium for assaying labile factor (factor V) because its response to added labile factor corresponds quantitatively to that of plasma from patients with congenital deficiency of this factor. Such an agreement is not obtained with plasma stored at 37°C. The stability of labile factor is closely associated with ionized calcium. The addition of thrombin to fresh oxalated plasma causes an apparent hyperactivity of labile factor, but this is completely removed by adsorption with Ca3(PO)2. Oxalated plasma when adsorbed with Ca3(PO4)2 before treatment with thrombin does not develop this adventitious activity, nor does it occur in stored plasma treated with thrombin. The seemingly high labile factor activity in serum can be explained by the activation of this factor which is independent of labile factor but acts synergistically with it. The true labile factor concentration can be determined only after the accelerator is removed by adsorption with Ca3(PO4)2. A close agreement between the consumption of prothrombin and the loss of labile factor during clotting is observed. PMID:13738700

  6. Quantification of Emission Factor Uncertainty

    EPA Science Inventory

    Emissions factors are important for estimating and characterizing emissions from sources of air pollution. There is no quantitative indication of uncertainty for these emission factors, most factors do not have an adequate data set to compute uncertainty, and it is very difficult...

  7. Factor Analysis via Components Analysis

    ERIC Educational Resources Information Center

    Bentler, Peter M.; de Leeuw, Jan

    2011-01-01

    When the factor analysis model holds, component loadings are linear combinations of factor loadings, and vice versa. This interrelation permits us to define new optimization criteria and estimation methods for exploratory factor analysis. Although this article is primarily conceptual in nature, an illustrative example and a small simulation show…

  8. Factor Analysis of Intern Effectiveness

    ERIC Educational Resources Information Center

    Womack, Sid T.; Hannah, Shellie Louise; Bell, Columbus David

    2012-01-01

    Four factors in teaching intern effectiveness, as measured by a Praxis III-similar instrument, were found among observational data of teaching interns during the 2010 spring semester. Those factors were lesson planning, teacher/student reflection, fairness & safe environment, and professionalism/efficacy. This factor analysis was as much of a…

  9. Risk Factor Assessment Branch (RFAB)

    Cancer.gov

    The Risk Factor Assessment Branch (RFAB) focuses on the development, evaluation, and dissemination of high-quality risk factor metrics, methods, tools, technologies, and resources for use across the cancer research continuum, and the assessment of cancer-related risk factors in the population.

  10. Phonological Awareness: Factors of Influence

    ERIC Educational Resources Information Center

    Frohlich, Linda Paulina; Petermann, Franz; Metz, Dorothee

    2013-01-01

    Early child development is influenced by various genetic and environmental factors. This study aims to identify factors that affect the phonological awareness of preschool and first grade children. Based on a sample of 330 German-speaking children (mean age = 6.2 years) the following domains were evaluated: Parent factors, birth and pregnancy,…

  11. Von Willebrand factor processing.

    PubMed

    Brehm, Maria A

    2017-01-31

    Von Willebrand factor (VWF) is a multimeric glycoprotein essential for primary haemostasis that is produced only in endothelial cells and megakaryocytes. Key to VWF's function in recruitment of platelets to the site of vascular injury is its multimeric structure. The individual steps of VWF multimer biosynthesis rely on distinct posttranslational modifications at specific pH conditions, which are realized by spatial separation of the involved processes to different cell organelles. Production of multimers starts with translocation and modification of the VWF prepropolypeptide in the endoplasmic reticulum to produce dimers primed for glycosylation. In the Golgi apparatus they are further processed to multimers that carry more than 300 complex glycan structures functionalized by sialylation, sulfation and blood group determinants. Of special importance is the sequential formation of disulfide bonds with different functions in structural support of VWF multimers, which are packaged, stored and further processed after secretion. Here, all these processes are being reviewed in detail including background information on the occurring biochemical reactions.

  12. Proteolytic factors in exosomes.

    PubMed

    Shimoda, Masayuki; Khokha, Rama

    2013-05-01

    Exosomes are small microvesicles secreted from the late endosomal compartment of cells. Although an increasing body of evidence indicates that they play a pivotal role in cell-to-cell communication, the biological functions of exosomes are far from fully understood. Recent work has revealed detailed proteomic profiles of exosomes from cell lines and body fluids, which may provide clues to understanding their biological significance and general importance in human diseases. Metalloproteinases include the cell surface-anchored sheddases a disintegrin and metalloproteinases, as well as cell surface-bound and soluble matrix metalloproteinases and these extracellular proteases have been detected in exosomes by proteomic analyses. Exosomes play a key role in the transfer of proteins to other cells and metalloproteinases may provide a novel platform where ectodomain shedding by these membrane proteases alters the makeup of the recipient cell's surface. This review aims to address some of the facets of exosome biology with particular emphasis on the proteolytic factors and we discuss their potential involvement in human diseases, especially tumor biology.

  13. Human Factors in Training

    NASA Technical Reports Server (NTRS)

    Barshi, Immanuel; Byrne, Vicky; Arsintescu, Lucia; Connell, Erin; Sandor, Aniko

    2009-01-01

    Future space missions will be significantly longer than current shuttle missions and new systems will be more complex than current systems. Increasing communication delays between crews and Earth-based support means that astronauts need to be prepared to handle the unexpected on their own. As crews become more autonomous, their potential span of control and required expertise must grow to match their autonomy. It is not possible to train for every eventuality ahead of time on the ground, or to maintain trained skills across long intervals of disuse. To adequately prepare NASA personnel for these challenges, new training approaches, methodologies, and tools are required. This research project aims at developing these training capabilities. By researching established training principles, examining future needs, and by using current practices in space flight training as test beds, both in Flight Controller and Crew Medical domains, this research project is mitigating program risks and generating templates and requirements to meet future training needs. Training efforts in Fiscal Year 08 (FY08) strongly focused on crew medical training, but also began exploring how Space Flight Resource Management training for Mission Operations Directorate (MOD) Flight Controllers could be integrated with systems training for optimal Mission Control Center (MCC) operations. The Training Task addresses Program risks that lie at the intersection of the following three risks identified by the Project: (1) Risk associated with poor task design (2) Risk of error due to inadequate information (3) Risk associated with reduced safety and efficiency due to poor human factors design

  14. Human Factors in Training

    NASA Technical Reports Server (NTRS)

    Barshi, Immanuel; Byme, Vicky; Arsintescu, Lucia

    2008-01-01

    Future space missions will be significantly longer than current Shuttle missions and new systems will be more complex than current systems. Increasing communication delays between crews and Earth-based support means that astronauts need to be prepared to handle the unexpected on their own. As crews become more autonomous, their potential span of control and required expertise must grow to match their autonomy. It is not possible to train for every eventuality ahead of time on the ground, or to maintain trained skills across long intervals of disuse. To adequately prepare NASA personnel for these challenges, new training approaches, methodologies, and tools are required. This research project aims at developing these training capabilities. Training efforts in FY07 strongly focused on crew medical training, but also began exploring how Space Flight Resource Management training for Mission Operations Directorate (MOD) Flight Controllers could be integrated with systems training for optimal Mission Control Center operations. Beginning in January 2008, the training research effort will include team training prototypes and tools. The Training Task addresses Program risks that lie at the intersection of the following three risks identified by the Project: 1) Risk associated with poor task design; 2) Risk of error due to inadequate information; 3) Risk associated with reduced safety and efficiency due to poor human factors design.

  15. Human Factors in Training

    NASA Technical Reports Server (NTRS)

    Barshi, Immanuel; Byrne, Vicky; Arsintescu, Lucia; Connell, Erin

    2010-01-01

    Future space missions will be significantly longer than current shuttle missions and new systems will be more complex than current systems. Increasing communication delays between crews and Earth-based support means that astronauts need to be prepared to handle the unexpected on their own. As crews become more autonomous, their potential span of control and required expertise must grow to match their autonomy. It is not possible to train for every eventuality ahead of time on the ground, or to maintain trained skills across long intervals of disuse. To adequately prepare NASA personnel for these challenges, new training approaches, methodologies, and tools are required. This research project aims at developing these training capabilities. By researching established training principles, examining future needs, and by using current practices in space flight training as test beds, both in Flight Controller and Crew Medical domains, this research project is mitigating program risks and generating templates and requirements to meet future training needs. Training efforts in Fiscal Year 09 (FY09) strongly focused on crew medical training, but also began exploring how Space Flight Resource Management training for Mission Operations Directorate (MOD) Flight Controllers could be integrated with systems training for optimal Mission Control Center (MCC) operations. The Training Task addresses Program risks that lie at the intersection of the following three risks identified by the Project: 1) Risk associated with poor task design; 2) Risk of error due to inadequate information; and 3) Risk associated with reduced safety and efficiency due to poor human factors design.

  16. Factor XII Contact Activation.

    PubMed

    Naudin, Clément; Burillo, Elena; Blankenberg, Stefan; Butler, Lynn; Renné, Thomas

    2017-03-27

    Contact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation-associated disease states.

  17. [Study of the polymorphism R353Q in the coagulation factor VII gene and the N700S in the thrombospondin-1 gene in young patients with acute myocardial infarction].

    PubMed

    Valades-Mejía, María Guadalupe; Domínguez-López, María Lilia; Aceves-Chimal, José Luis; Miranda, Alfredo Leaños; Majluf-Cruz, Abraham; Isordia-Salas, Irma

    2014-01-01

    Antecedentes: el infarto agudo de miocardio es la principal causa de morbilidad y mortalidad en el mundo, y resulta de la combinación de factores modificables y genéticos. Se ha propuesto que el polimorfismo R353Q en el gen del factor VII de la coagulación representa un factor protector en contra del infarto agudo de miocardio, mientras que el polimorfismo N700S en el gen de la trombospondina-1 (TSP- 1) incrementa el riesgo; sin embargo, los resultados aún suscitan controversia. Objetivo: determinar la posible asociación de los polimorfismos R353Q y del N700S con el infarto agudo de miocardio en pacientes mexicanos menores de 45 años. Material y métodos: estudio de casos y controles que incluyó 252 pacientes con diagnóstico de infarto agudo de miocardio y 252 individuos aparentemente sanos sin antecedentes de enfermedad coronaria, pareados por edad y sexo. Los polimorfismos R353Q N700S se determinaron en todos los participantes por medio de PCR-RFLP. Resultados: no se observó diferencia estadística en la distribución genotípica del polimorfismo R353Q del FVII entre los grupos con infarto agudo de miocardio y el grupo control (p = 0.06). Se encontró una distribución genotípica similar del polimorfismo N700S en ambos grupos (p = 0.50). Se identificaron como factores de riesgo independiente para infarto agudo de miocardio: hipertensión arterial, diabetes mellitus, antecedentes heredofamiliares para enfermedad coronaria y dislipidemia. Conclusiones: los polimorfismos R353Q y N700S no representan un factor protector o de riesgo, respectivamente, para infarto agudo de miocardio en pacientes jóvenes mexicanos. Palabras clave: factor VII de la coagulación, trombospondina-1, infarto agudo de miocardio, polimorfismo.

  18. Respiratory factors limiting exercise.

    PubMed

    Bye, P T; Farkas, G A; Roussos, C

    1983-01-01

    The question of respiratory factors limiting exercise has been examined in terms of possible limitations arising from the function of gas exchange, the respiratory mechanics, the energetics of the respiratory muscles, or the development of respiratory muscle fatigue. Exercise capacity is curtailed in the presence of marked hypoxia, and this is readily observed in patients with chronic airflow limitation and interstitial lung disease and in some athletes at high intensities of exercise. In patients with interstitial lung disease, gas exchange abnormality--partly the result of diffusion disequilibrium for oxygen transfer--occurs during exercise despite abnormally high ventilations. In contrast, in certain athletes arterial hypoxemia has been documented during heavy exercise, apparently as a result of relative hypoventilation. During strenuous exercise the maximum expiratory flow volume curves are attained both by patients with chronic airflow limitation and by normal subjects, in particular when they breathe dense gas, so that a mechanical constraint is imposed on further increases in ventilation. Similarly, the force velocity characteristics of the inspiratory muscles may also impose a constraint to further increases in inspiratory flows that affects the ability to increase ventilation. In addition, the oxygen cost of maintaining high ventilations is large. Analysis of results from blood flow experiments reveal a substantial increase in blood flow to the respiratory muscles during exercise, with the result that oxygen supply to the rest of the body may be lessened. Alternatively, high exercise ventilations may not be sustained indefinitely owing to the development of respiratory muscle fatigue that results in hypoventilation and reduced arterial oxygen tension.

  19. Platelet Activating Factor: A Growth Factor for Breast Cancer

    DTIC Science & Technology

    2006-09-01

    Factor for Breast Cancer PRINCIPAL INVESTIGATOR: Larry W. Daniel, Ph.D. CONTRACTING ORGANIZATION: Wake Forest University...A Growth Factor for Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-04-1-0682 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Larry W...Relevance: If PAF is found to be a growth and angiogenic factor for breast cancer cells, these studies can be followed up by in vivo studies in nude

  20. Risk factors for periodontal disease.

    PubMed

    Genco, Robert J; Borgnakke, Wenche S

    2013-06-01

    Risk factors play an important role in an individual's response to periodontal infection. Identification of these risk factors helps to target patients for prevention and treatment, with modification of risk factors critical to the control of periodontal disease. Shifts in our understanding of periodontal disease prevalence, and advances in scientific methodology and statistical analysis in the last few decades, have allowed identification of several major systemic risk factors for periodontal disease. The first change in our thinking was the understanding that periodontal disease is not universal, but that severe forms are found only in a portion of the adult population who show abnormal susceptibility. Analysis of risk factors and the ability to statistically adjust and stratify populations to eliminate the effects of confounding factors have allowed identification of independent risk factors. These independent but modifiable, risk factors for periodontal disease include lifestyle factors, such as smoking and alcohol consumption. They also include diseases and unhealthy conditions such as diabetes mellitus, obesity, metabolic syndrome, osteoporosis, and low dietary calcium and vitamin D. These risk factors are modifiable and their management is a major component of the contemporary care of many periodontal patients. Genetic factors also play a role in periodontal disease and allow one to target individuals for prevention and early detection. The role of genetic factors in aggressive periodontitis is clear. However, although genetic factors (i.e., specific genes) are strongly suspected to have an association with chronic adult periodontitis, there is as yet no clear evidence for this in the general population. It is important to pursue efforts to identify genetic factors associated with chronic periodontitis because such factors have potential in identifying patients who have a high susceptibility for development of this disease. Many of the systemic risk factors

  1. Growth factors in synaptic function

    PubMed Central

    Poon, Vivian Y.; Choi, Sojoong; Park, Mikyoung

    2013-01-01

    Synapses are increasingly recognized as key structures that malfunction in disorders like schizophrenia, mental retardation, and neurodegenerative diseases. The importance and complexity of the synapse has fuelled research into the molecular mechanisms underlying synaptogenesis, synaptic transmission, and plasticity. In this regard, neurotrophic factors such as netrin, Wnt, transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and others have gained prominence for their ability to regulate synaptic function. Several of these factors were first implicated in neuroprotection, neuronal growth, and axon guidance. However, their roles in synaptic development and function have become increasingly clear, and the downstream signaling pathways employed by these factors have begun to be elucidated. In this review, we will address the role of these factors and their downstream effectors in synaptic function in vivo and in cultured neurons. PMID:24065916

  2. Women's Career Success: A Factor Analytic Study of Contributing Factors.

    ERIC Educational Resources Information Center

    Gaskill, LuAnn Ricketts

    1991-01-01

    A survey of 466 women employed in retailing received 205 responses identifying (1) factors influencing the success and advancement of women in retailing and (2) how those factors differ for women in upper versus middle positions. Upper-level executives placed more importance on ambition and abilities; midlevel executives credited opportunity and…

  3. Factorized molecular wave functions: Analysis of the nuclear factor

    SciTech Connect

    Lefebvre, R.

    2015-06-07

    The exact factorization of molecular wave functions leads to nuclear factors which should be nodeless functions. We reconsider the case of vibrational perturbations in a diatomic species, a situation usually treated by combining Born-Oppenheimer products. It was shown [R. Lefebvre, J. Chem. Phys. 142, 074106 (2015)] that it is possible to derive, from the solutions of coupled equations, the form of the factorized function. By increasing artificially the interstate coupling in the usual approach, the adiabatic regime can be reached, whereby the wave function can be reduced to a single product. The nuclear factor of this product is determined by the lowest of the two potentials obtained by diagonalization of the potential matrix. By comparison with the nuclear wave function of the factorized scheme, it is shown that by a simple rectification, an agreement is obtained between the modified nodeless function and that of the adiabatic scheme.

  4. Effects of astragalosides from Radix Astragali on high glucose-induced proliferation and extracellular matrix accumulation in glomerular mesangial cells

    PubMed Central

    CHEN, XIAO; WANG, DONG-DONG; WEI, TONG; HE, SU-MEI; ZHANG, GUAN-YING; WEI, QUN-LI

    2016-01-01

    Diabetic nephropathy (DN) exhibits a deteriorating course that may lead to end-stage renal failure. Astragalosides have been clinically tested for the treatment of DN, but the mechanism is unclear at present. In this study, the effects of astragalosides were investigated on high glucose-induced proliferation and expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), type IV collagen (colIV) and fibronectin (FN) in glomerular mesangial cells (MCs). Cell proliferation was determined by 5-bromo-2′-deoxyuridine assay, and the expression of TGF-β1, CTGF, colIV and FN mRNA and proteins in MCs was detected by reverse transcription-polymerase chain reaction and ELISA assay, respectively. The results showed that high glucose clearly induced the proliferation of MCs and increased the expression of TGF-β1, CTGF, colIV and FN. Treatment with 50, 100, 200 µg/ml astragalosides inhibited cell proliferation and the expression of TGF-β1, CTGF, colIV and FN induced by high glucose. Thus, it is concluded that astragalosides inhibit the increased cell proliferation and expression of major extracellular matrix proteins that are induced by high glucose, indicating their value for the prophylaxis and therapy of DN. PMID:27313676

  5. Effect of astilbin on experimental diabetic nephropathy in vivo and in vitro.

    PubMed

    Li, Gui-Sheng; Jiang, Wang-Lin; Yue, Xi-Dian; Qu, Gui-Wu; Tian, Jing-Wei; Wu, Juan; Fu, Feng-Hua

    2009-11-01

    Astilbin, a flavonoid compound, was isolated from the rhizome of Smilax glabra Roxb. This study was conducted to investigate the efficacy of astilbin on experimental diabetic nephropathy (DN) in vivo and in vitro and its possible mechanisms. Astilbin was added in high glucose stimulated HK-2 cells, streptozotocin-induced experimental DN, randomized to receive intragastric ( I. G.) astilbin to observe its anti-renal lesion effect. Results showed that astilbin inhibited high glucose stimulated HK-2 cell production of transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in vitro, especially CTGF; analogic results was also found in vivo. I. G. of astilbin 2.5 mg/kg or 5 mg/kg significantly ameliorated renal function, reduced kidney index, while it increased body weight and survival time in animals. In addition there was no significant difference in blood glucose level between the STZ-treated group and the astilbin groups. Furthermore, astilbin ameliorated the pathological progress of renal morphology. Astilbin can exert an early renal protective role to DN, inhibit production of TGF-beta1 and especially of CTGF. We suggest that astilbin inhibition of CTGF may be a potential target in DN therapy. This work provides the first evidence for astilbin as a new candidate of DN therapeutic medicine.

  6. Factors That Influence Teacher Attrition.

    ERIC Educational Resources Information Center

    Gonzalez, Patricia

    1995-01-01

    External, employment, and personal factors which influence teacher decisions to stay, leave, or transfer from teaching assignments are discussed, with emphasis on special education teachers. Factors attributed to teacher attrition in urban and rural environments also are briefly reviewed, along with attrition of related services professionals.…

  7. Eight Factors in School Vitality.

    ERIC Educational Resources Information Center

    Strommen, Merton P.

    1980-01-01

    A survey of 30 National Catholic Educational Association Schools examined their ability to make needed program changes according to Davis' eight factors: Awareness of Need, Resistances, Values, Information, Ability, Timing, Circumstances, and Yield. This article compares a vital, growing school and a declining one on these eight factors.…

  8. Estimation of Unattenuated Factor Loadings.

    ERIC Educational Resources Information Center

    Woodward, Todd S.; Hunter, Michael A.

    1999-01-01

    Demonstrates that traditional exploratory factor analytic methods, when applied to correlation matrices, cannot be used to estimate unattenuated factor loadings. Presents a mathematical basis for the accurate estimation of such values when the disattenuated correlation matrix or the covariance matrix is used as input. Explains how the equations…

  9. Research Needs for Human Factors.

    ERIC Educational Resources Information Center

    Army Research Inst. for the Behavioral and Social Sciences, Arlington, VA.

    Human factors engineering can be defined as the application of scientific principles, methods, and data drawn from a variety of disciplines to the development of engineering systems in which people play a significant role. Since human factors issues arise in every domain in which humans interact with the products of a technological society, six…

  10. Factors That Shape Design Thinking

    ERIC Educational Resources Information Center

    Gray, Colin M.

    2013-01-01

    A wide range of design literature discusses the role of the studio and its related pedagogy in the development of design thinking. Scholars in a variety of design disciplines pose a number of factors that potentially affect this development process, but a full understanding of these factors as experienced from a critical pedagogy or student…

  11. Human Factors in CAI Design.

    ERIC Educational Resources Information Center

    Rambally, Gerard K.; Rambally, Rodney S.

    1987-01-01

    Identifies human factor issues involved in the student-computer interface in computer assisted instruction and makes specific recommendations for screen design. Factors considered include simplicity, spaciousness, relevance, standardization, changing display screen contents, color coding, shape and size coding, and brightness coding. (Author/LRW)

  12. Statistical Factors in Complexation Reactions.

    ERIC Educational Resources Information Center

    Chung, Chung-Sun

    1985-01-01

    Four cases which illustrate statistical factors in complexation reactions (where two of the reactants are monodentate ligands) are presented. Included are tables showing statistical factors for the reactions of: (1) square-planar complexes; (2) tetrahedral complexes; and (3) octahedral complexes. (JN)

  13. Matrix factorizations and elliptic fibrations

    NASA Astrophysics Data System (ADS)

    Omer, Harun

    2016-09-01

    I use matrix factorizations to describe branes at simple singularities of elliptic fibrations. Each node of the corresponding Dynkin diagrams of the ADE-type singularities is associated with one indecomposable matrix factorization which can be deformed into one or more factorizations of lower rank. Branes with internal fluxes arise naturally as bound states of the indecomposable factorizations. Describing branes in such a way avoids the need to resolve singularities. This paper looks at gauge group breaking from E8 fibers down to SU (5) fibers due to the relevance of such fibrations for local F-theory GUT models. A purpose of this paper is to understand how the deformations of the singularity are understood in terms of its matrix factorizations. By systematically factorizing the elliptic fiber equation, this paper discusses geometries which are relevant for building semi-realistic local models. In the process it becomes evident that breaking patterns which are identical at the level of the Kodaira type of the fibers can be inequivalent at the level of matrix factorizations. Therefore the matrix factorization picture supplements information which the conventional less detailed descriptions lack.

  14. [Risk factors for arterial disease].

    PubMed

    Madoery, Roberto; Rubin, Graciela; Luquez, Hugo; Luquez, Cecilia; Cravero, Cecilia

    2004-01-01

    The risk factors of arterial disease (FREA) predict a future damage over the vascular system of the human body. Its detection are considered a key for the diagnostic as well as for the preventive and even curative strategies. For a long time, scientist considered those factors originated as a consecuence of large studies during the middle of the last century, with current validity up to our days. A simple classification spoke of them as traditionals. Further investigations described the so called new or emergents.factors that where joint together accordingly to their actions: coagulation factors, psicosocial, inflamatories and infectious. A recent classification, taking into account the type of impact, divided them into; causatives, predisposals and conditionals. Also, it was described a mechanism, the oxidative power, with consecuences over the endothelium, in the last part of the process. Before, another mechanism was described: the insulin resistance and the hiperinsulinism, bases for the Metabolic Syndrome, that includes a number of traditional risk factors.

  15. Human factors in visualization research.

    PubMed

    Tory, Melanie; Möller, Torsten

    2004-01-01

    Visualization can provide valuable assistance for data analysis and decision making tasks. However, how people perceive and interact with a visualization tool can strongly influence their understanding of the data as well as the system's usefulness. Human factors therefore contribute significantly to the visualization process and should play an important role in the design and evaluation of visualization tools. Several research initiatives have begun to explore human factors in visualization, particularly in perception-based design. Nonetheless, visualization work involving human factors is in its infancy, and many potentially promising areas have yet to be explored. Therefore, this paper aims to 1) review known methodology for doing human factors research, with specific emphasis on visualization, 2) review current human factors research in visualization to provide a basis for future investigation, and 3) identify promising areas for future research.

  16. Knockout, Transfer and Spectroscopic Factors

    NASA Astrophysics Data System (ADS)

    Kemper, Kirby; Keeley, Nicholas; Rusek, Krzysztof

    2011-10-01

    As derived quantities rather than observables, spectroscopic factors extracted from fits to data are model dependent. The main source of uncertainty is the choice of binding potential, but other factors such as adequate modeling of the reaction mechanism, the Perey effect, choice of distorting nuclear potentials etc. can also play a significant role. Recently, there has been some discussion of apparent discrepancies in spectroscopic factors derived from knockout reactions compared to those obtained from low-energy direct reactions. It should be possible to reconcile these discrepancies and we explore this prospect by attempting to describe the 10Be(d,t)9Be data of Nucl. Phys. A157, 305 (1970) using the 10Be/9Be form factors from a recent knockout study, Phys. Rev. Lett. 106, 162502 (2011). The influence of such factors as choice of distorting potentials and multi-step reactions paths will be explored.

  17. Great Lakes management: Ecological factors

    NASA Astrophysics Data System (ADS)

    Sonzogni, W. C.; Robertson, A.; Beeton, A. M.

    1983-11-01

    Although attempts to improve the quality of the Great Lakes generally focus on chemical pollution, other factors are important and should be considered Ecological factors, such as invasion of the lakes by foreign species, habitat changes, overfishing, and random variations in organism populations, are especially influential. Lack of appreciation of the significance of ecological factors stems partly from the inappropriate application of the concept of eutrophication to the Great Lakes. Emphasis on ecological factors is not intended to diminish the seriousness of pollution, but rather to point out that more cost-effective management, as well as more realistic expectations of management efforts by the public, should result from an ecosystem management approach in which ecological factors are carefully considered.

  18. Factoring in Factor VIII With Acute Ischemic Stroke.

    PubMed

    Siegler, James E; Samai, Alyana; Albright, Karen C; Boehme, Amelia K; Martin-Schild, Sheryl

    2015-10-01

    There is growing research interest into the etiologies of cryptogenic stroke, in particular as it relates to hypercoagulable states. An elevation in serum levels of the procoagulant factor VIII is recognized as one such culprit of occult cerebral infarctions. It is the objective of the present review to summarize the molecular role of factor VIII in thrombogenesis and its clinical use in the diagnosis and prognosis of acute ischemic stroke. We also discuss the utility of screening for serum factor VIII levels among patients at risk for, or those who have experienced, ischemic stroke.

  19. Corrosion effects on friction factors

    SciTech Connect

    Magleby, H.L.; Shaffer, S.J.

    1996-03-01

    This paper presents the results of NRC-sponsored material specimen tests that were performed to determine if corrosion increases the friction factors of sliding surfaces of motor-operated gate valves, which could require higher forces to close and open safety-related valves when subjected to their design basis differential pressures. Friction tests were performed with uncorroded specimens and specimens subjected to accelerated corrosion. Preliminary tests at ambient conditions showed that corrosion increased the friction factors, indicating the need for additional tests duplicating valve operating parameters at hot conditions. The additional tests showed friction factors of corroded specimens were 0.1 to 0.2 higher than for uncorroded specimens, and that the friction factors of the corroded specimens were not very dependent on contact stress or corrosion film thickness. The measured values of friction factors for the three corrosion films tested (simulating three operating times) were in the range of 0.3 to 0.4. The friction factor for even the shortest simulated operating time was essentially the same as the others, indicating that the friction factors appear to reach a plateau and that the plateau is reached quickly.

  20. Impact factors: uses and abuses.

    PubMed

    Neuberger, James; Counsell, Christopher

    2002-03-01

    Quantitative assessment of the scientific merit of journals and articles is being used increasingly to assess and compare researchers and institutions. The most commonly used measure is the 2 year Impact Factor, which broadly reflects the number of times each article in the journal has been cited over the previous 2 years. There are clear limitations to the use of such measures - not least, Impact Factors reflect the journal not the article, vary with time and correlate only poorly with perceived excellence. Simple comparison of impact factors in different specialties may be misleading. Review journals often have higher Impact Factors than those with original data. Both authors and editors can try to manipulate journal Impact Factors. However, despite valid concerns, Impact Factors are widely used and offer, at present, the best simple tool for comparison of output. Like all measures, the use of Impact Factors has to be tempered with knowledge of their limitations and common sense used in interpreting any data based on any analysis.

  1. Factors controlling pancreatic islet neogenesis.

    PubMed Central

    Vinik, A.; Pittenger, G.; Rafaeloff, R.; Rosenberg, L.

    1992-01-01

    We have established a model in which cellophane wrapping induces reiteration of the normal ontogeny of beta-cell differentiation from ductal tissue. The secretion of insulin is physiologic and coordinated to the needs of the animal. Streptozotocin-induced diabetes in hamsters can be "cured" at least half the time. There appears to be activation of growth factor(s) within the pancreas, acting in an autocrine, paracrine, or juxtacrine manner to induce ductal cell proliferation and differentiation into functioning beta cells. Given the results of our studies to date, it does not seem premature to envisage new approaches to the treatment of diabetes mellitus. Identification of the factor(s) regulating islet-cell proliferation and differentiation in our model may permit islets to be grown in culture. This concept could be extended to induce endocrine cell differentiation in vitro as well. Furthermore, islet-cell growth factors could be used to provide "trophic support" to islet transplants as a means of maintaining graft viability. There may also be greater scope for gene therapy when the growth factor(s) have been isolated, purified, sequenced, and cloned. Images FIG. 2 FIG. 5 FIG. 6 FIG. 9 PMID:1364089

  2. Factors Affecting Medical Service Quality

    PubMed Central

    MOSADEGHRAD, Ali Mohammad

    2014-01-01

    Abstract Background A better understanding of factors influencing quality of medical service can pinpoint better strategies for quality assurance in medical services. This study aimed to identify factors affecting the quality of medical services provided by Iranian physicians. Methods Exploratory in-depth individual interviews were conducted with sixty-four physicians working in various medical institutions in Iran. Results Individual, organizational and environmental factors enhance or inhibit the quality of medical services. Quality of medical services depends on the personal factors of the physician and patient, and factors pertaining to the healthcare setting and the broader environment. Conclusion Differences in internal and external factors such as availability of resources, patient cooperation and collaboration among providers affect the quality of medical services and patient outcomes. Supportive leadership, proper planning, education and training and effective management of resources and processes improve the quality of medical services. This article contributes to healthcare theory and practice by developing a conceptual framework for understanding factors that influence medical services quality. PMID:26060745

  3. GATA factors in endocrine neoplasia

    PubMed Central

    Pihlajoki, Marjut; Färkkilä, Anniina; Soini, Tea; Heikinheimo, Markku; Wilson, David B.

    2015-01-01

    GATA transcription factors are structurally-related zinc finger proteins that recognize the consensus DNA sequence WGATAA (the GATA motif), an essential cis-acting element in the promoters and enhancers of many genes. These transcription factors regulate cell fate specification and differentiation in a wide array of tissues. As demonstrated by genetic analyses of mice and humans, GATA factors play pivotal roles in the development, homeostasis, and function of several endocrine organs including the adrenal cortex, ovary, pancreas, parathyroid, pituitary, and testis. Additionally, GATA factors have been shown to be mutated, overexpressed, or underexpressed in a variety of endocrine tumors (e.g., adrenocortical neoplasms, parathyroid tumors, pituitary adenomas, and sex cord stromal tumors). Emerging evidence suggests that GATA factors play a direct role in the initiation, proliferation, or propagation of certain endocrine tumors via modulation of key developmental signaling pathways implicated in oncogenesis, such as the WNT/β-catenin and TGFβ pathways. Altered expression or function of GATA factors can also affect the metabolism, ploidy, and invasiveness of tumor cells. This article provides an overview of the role of GATA factors in endocrine neoplasms. Relevant animal models are highlighted. PMID:26027919

  4. Sequence Factorization with Multiple References

    PubMed Central

    Wandelt, Sebastian; Leser, Ulf

    2015-01-01

    The success of high-throughput sequencing has lead to an increasing number of projects which sequence large populations of a species. Storage and analysis of sequence data is a key challenge in these projects, because of the sheer size of the datasets. Compression is one simple technology to deal with this challenge. Referential factorization and compression schemes, which store only the differences between input sequence and a reference sequence, gained lots of interest in this field. Highly-similar sequences, e.g., Human genomes, can be compressed with a compression ratio of 1,000:1 and more, up to two orders of magnitude better than with standard compression techniques. Recently, it was shown that the compression against multiple references from the same species can boost the compression ratio up to 4,000:1. However, a detailed analysis of using multiple references is lacking, e.g., for main memory consumption and optimality. In this paper, we describe one key technique for the referential compression against multiple references: The factorization of sequences. Based on the notion of an optimal factorization, we propose optimization heuristics and identify parameter settings which greatly influence 1) the size of the factorization, 2) the time for factorization, and 3) the required amount of main memory. We evaluate a total of 30 setups with a varying number of references on data from three different species. Our results show a wide range of factorization sizes (optimal to an overhead of up to 300%), factorization speed (0.01 MB/s to more than 600 MB/s), and main memory usage (few dozen MB to dozens of GB). Based on our evaluation, we identify the best configurations for common use cases. Our evaluation shows that multi-reference factorization is much better than single-reference factorization. PMID:26422374

  5. Genetics Home Reference: factor V Leiden thrombophilia

    MedlinePlus

    ... Conditions factor V Leiden thrombophilia factor V Leiden thrombophilia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Factor V Leiden thrombophilia is an inherited disorder of blood clotting . Factor ...

  6. [Cardiovascular risk factors in women].

    PubMed

    Cengel, Atiye

    2010-03-01

    It is estimated that at least 80% of patients with cardiovascular disease (CVD) have conventional risk factors and optimization of these risk factors can reduce morbidity and mortality due to this disease considerably. Contemporary women have increased burden of some of these risk factors such as obesity, metabolic syndrome and smoking. Turkish women have a worse CV risk profile than Turkish men in some aspects. Risk stratification systems such as Framingham have a tendency of underestimating the risk in women. Coronary artery disease remains in vessel wall for a longer period of time in women; therefore obstructive disease appear later in their lifespan necessitating risk stratification systems for estimating their lifetime risk.

  7. Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus

    PubMed Central

    Matta, Ajay; Karim, M. Zia; Isenman, David E.; Erwin, W. Mark

    2017-01-01

    Degenerative disc disease (DDD) is associated with spinal pain often leading to long-term disability. However, the non-chondrodystrophic canine intervertebral disc is protected from the development of DDD, ostensibly due to its retention of notochordal cells (NC) in the nucleus pulposus (NP). In this study, we hypothesized that secretome analysis of the NC-rich NP will lead to the identification of key proteins that delay the onset of DDD. Using mass-spectrometry, we identified 303 proteins including components of TGFβ- and Wnt-signaling, anti-angiogeneic factors and proteins that inhibit axonal ingrowth in the bioactive fractions of serum free, notochordal cell derived conditioned medium (NCCM). Ingenuity Pathway Analysis revealed TGFβ1 and CTGF as major hubs in protein interaction networks. In vitro treatment with TGFβ1 and CTGF promoted the synthesis of healthy extra-cellular matrix proteins, increased cell proliferation and reduced cell death in human degenerative disc NP cells. A single intra-discal injection of recombinant TGFβ1 and CTGF proteins in a pre-clinical rat-tail disc injury model restored the NC and stem cell rich NP. In conclusion, we demonstrate the potential of TGFβ1 and CTGF to mitigate the progression of disc degeneration and the potential use of these molecules in a molecular therapy to treat the degenerative disc. PMID:28358123

  8. Mechanisms underlying the cardiac antifibrotic effects of losartan metabolites

    PubMed Central

    Miguel-Carrasco, José Luis; Beaumont, Javier; San José, Gorka; Moreno, María U.; López, Begoña; González, Arantxa; Zalba, Guillermo; Díez, Javier; Fortuño, Ana; Ravassa, Susana

    2017-01-01

    Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-β1-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts. PMID:28157237

  9. A multifunctional protein EWS regulates the expression of Drosha and microRNAs.

    PubMed

    Kim, K Y; Hwang, Y J; Jung, M-K; Choe, J; Kim, Y; Kim, S; Lee, C-J; Ahn, H; Lee, J; Kowall, N W; Kim, Y K; Kim, J-I; Lee, S B; Ryu, H

    2014-01-01

    EWS (Ewing's Sarcoma) gene encodes an RNA/DNA-binding protein that is ubiquitously expressed and involved in various cellular processes. EWS deficiency leads to impaired development and early senescence through unknown mechanisms. We found that EWS regulates the expression of Drosha and microRNAs (miRNAs). EWS deficiency resulted in increased expression of Drosha, a well-known microprocessor, and increased levels of miR-29b and miR-18b. Importantly, miR-29b and miR-18b were directly involved in the post-transcriptional regulation of collagen IV alpha 1 (Col4a1) and connective tissue growth factor (CTGF) in EWS knock-out (KO) mouse embryonic fibroblast cells. The upregulation of Drosha, miR-29b and miR-18b and the sequential downregulation of Col4a1 and CTGF contributed to the deregulation of dermal development in EWS KO mice. Otherwise, knockdown of Drosha rescued miRNA-dependent downregulation of Col4a1 and CTGF proteins. Taken together, our data indicate that EWS is involved in post-transcriptional regulation of Col4a1 and CTGF via a Drosha-miRNA-dependent pathway. This finding suggests that EWS has a novel role in dermal morphogenesis through the modulation of miRNA biogenesis.

  10. Factorization-based texture segmentation

    SciTech Connect

    Yuan, Jiangye; Wang, Deliang; Cheriyadat, Anil M.

    2015-06-17

    This study introduces a factorization-based approach that efficiently segments textured images. We use local spectral histograms as features, and construct an M × N feature matrix using M-dimensional feature vectors in an N-pixel image. Based on the observation that each feature can be approximated by a linear combination of several representative features, we factor the feature matrix into two matrices-one consisting of the representative features and the other containing the weights of representative features at each pixel used for linear combination. The factorization method is based on singular value decomposition and nonnegative matrix factorization. The method uses local spectral histograms to discriminate region appearances in a computationally efficient way and at the same time accurately localizes region boundaries. Finally, the experiments conducted on public segmentation data sets show the promise of this simple yet powerful approach.

  11. Predisposition Factors in Anorexia Nervosa.

    ERIC Educational Resources Information Center

    Nagel, K. L.; Jones, Karen H.

    1992-01-01

    Reviews literature concerned with investigating psychiatric disturbances and genetic variables hypothesized as predisposing factors in etiology of anorexia nervosa. Gives particular emphasis to research which discusses association between anorexia nervosa and depression. Reviews psychopharmacological evidence and family genetics studies. Offers…

  12. Salivary Gland Cancer: Risk Factors

    MedlinePlus

    ... continue reading this guide. ‹ Salivary Gland Cancer - Medical Illustrations up Salivary Gland Cancer - Screening › f t k ... Net Guide Salivary Gland Cancer Introduction Statistics Medical Illustrations Risk Factors Screening Symptoms and Signs Diagnosis Subtypes ...

  13. Hidden Risk Factors for Women

    MedlinePlus

    ... previous history of clots in the legs (deep vein thrombosis) and livedo reticularis, a mottled purplish discoloration of the skin. “Risk factors are cumulative,” Dr. Kittner adds. “Reducing even one ...

  14. Cabin crew stress factors examined.

    PubMed

    Barayan, O S

    1991-05-01

    The impact of reduced cockpit crew on the cabin crew in commercial airlines is examined. One hundred cabin crew members participated in a study to determine what stressors are present in contemporary transport aircraft, the extent of differences in rating context-related and task-related stressors, and the effect of peak versus normal periods of duty time on stress factors. Results indicate that under peak period conditions, context-related factors are more stressful than task-related factors. Recommendations to alleviate cabin crew stress factors include training to maximize crew knowledge and abilities, elevate cabin crew to the same status as cockpit crew, improve the cabin crew certification program, and expose cabin crew to cockpit crew procedures to foster better communication and enhance safety.

  15. Factorization-based texture segmentation

    DOE PAGES

    Yuan, Jiangye; Wang, Deliang; Cheriyadat, Anil M.

    2015-06-17

    This study introduces a factorization-based approach that efficiently segments textured images. We use local spectral histograms as features, and construct an M × N feature matrix using M-dimensional feature vectors in an N-pixel image. Based on the observation that each feature can be approximated by a linear combination of several representative features, we factor the feature matrix into two matrices-one consisting of the representative features and the other containing the weights of representative features at each pixel used for linear combination. The factorization method is based on singular value decomposition and nonnegative matrix factorization. The method uses local spectral histogramsmore » to discriminate region appearances in a computationally efficient way and at the same time accurately localizes region boundaries. Finally, the experiments conducted on public segmentation data sets show the promise of this simple yet powerful approach.« less

  16. Factors influencing dust suppressant effectiveness

    SciTech Connect

    Copeland, C.R.; Eisele, T.C.; Chesney, D.J.; Kawatra, S.K.

    2008-11-15

    Water sprays are a common method used to reduce particulate matter (PM) emissions. Various factors such as wettability, surface area coverage, fine particle engulfment rates, interparticle adhesion forces, suppressant penetration and suppressant longevity have all been suggested as critical factors in achieving effective PM control. However, it has not been established which of these factors are the most important. Experimental work indicated that suppressant penetration is the most critical of these factors. The length of time after application that suppressants were effective was also improved by using hygroscopic reagents that retained moisture to prevent evaporation. Maximizing suppressant penetration and improving suppressant longevity led to an average 86% reduction in PM10 concentrations in laboratory dust tower tests.

  17. Radiant-interchange Configuration Factors

    NASA Technical Reports Server (NTRS)

    Hamilton, D C :; Morgan, W R

    1952-01-01

    A study is presented of the geometric configuration factors required for computing radiant heat transfer between opaque surfaces separated by a nonabsorbing medium and various methods of determining the configuration factors are discussed. Configuration-factor solutions available in the literature have been checked and the more complicated equations are presented as families of curves. Cases for point, line, and finite-area sources are worked out over a wide range of geometric proportions. These cases include several new configurations involving rectangles, triangles, and cylinders of finite length which are integrated and tabulated. An analysis is presented, in which configuration factors are employed of the radiant heat transfer to the rotor blades of a typical gas turbine under different conditions of temperature and pressure. (author)

  18. Formulas for Image Factor Scores

    ERIC Educational Resources Information Center

    Hakstian, A. Ralph

    1973-01-01

    Formulas are presented in this paper for computing scores associated with factors of G, the image covariance matrix, under three conditions. The subject of the paper is restricted to "pure" image analysis. (Author/NE)

  19. Environmental Factors Inducing Human Cancers

    PubMed Central

    Parsa, N

    2012-01-01

    Background An explosion of research has been done in discovering how human health is affected by environmental factors. I will discuss the impacts of environmental cancer causing factors and how they continue to cause multiple disruptions in cellular networking. Some risk factors may not cause cancer. Other factors initiate consecutive genetic mutations that would eventually alter the normal pathway of cellular proliferations and differentiation. Genetic mutations in four groups of genes; (Oncogenes, Tumor suppressor genes, Apoptosis genes and DNA repairing genes) play a vital role in altering the normal cell division. In recent years, molecular genetics have greatly increased our understanding of the basic mechanisms in cancer development and utilizing these molecular techniques for cancer screening, diagnosis, prognosis and therapies. Inhibition of carcinogenic exposures wherever possible should be the goal of cancer prevention programs to reduce exposures from all environmental carcinogens. PMID:23304670

  20. Research Needs for Human Factors

    DTIC Science & Technology

    1983-01-01

    Research Note 83-07 RESEARCH NEEDS FOR HUMAN FACTORS Conmmittee on Human Factors Cot ittee on Behavioral and Social Sciences and Education National... Research Council IIJanuary 1983 i ~ Approvted for Dublit rellease; distribution unlimited. __ A N- This report, as submitted by the contractor, has...CATALOG NUMBE -- Research Note 83-07 A2{>/)/.2 ? ___ 4. TITLE (e 5110) S. TyPE of REPORT & PERIOD COVERED Renearch Needs for Human Facotrs S. PERFORMING

  1. Human Factors in Aircraft Maintenance

    DTIC Science & Technology

    2001-03-01

    significant effect on the design of new systems but it can also mitigate problems found in the sub-optimal designs of current systems. 2. Human Factors...and parts 3. Airplane design and configuration 4. Job and task 5. Technical knowledge and skills 6. Factors affecting individual performance-e.g...software failures (e.g. documentation design ) were found. Note that there are typically multiple latent failures for each hazard pattern, so that

  2. Rank Revealing QR-Factorizations.

    DTIC Science & Technology

    1985-06-01

    amount to finding an appropriate column permutation of A. Perhaps the most well- known of these is the column pivoting strategy [2j. Although this... strategy is usually very effective in producing a triangular factor R with a small IIR2211, very little is known in theory about its behaviour and it can...is analogous to the strategy proposed in [6], in which the permutation of II is obtained via a QR-factorization with column pivoting applied to

  3. Industrial Power Factor Analysis Guidebook.

    SciTech Connect

    Electrotek Concepts.

    1995-03-01

    Power factor is a way of measuring the percentage of reactive power in an electrical system. Reactive power represents wasted energy--electricity that does no useful work because the electrical current is out of phase with the voltage. Reactive power is used by inductive loads (such as, motors, transformers, fluorescent lights, arc welders and induction furnaces) to sustain their magnetic fields. Electric systems with many motors exhibit low power factors, increased conductor and transformer losses, and lower voltages. Utilities must supply both active and reactive power and compensate for these losses. Power factor can be improved by the addition of shunt capacitors. Capacitors act in opposition to inductive loads, thereby minimizing the reactive power required to serve them. In raising the power factor, shunt capacitors release energy to the system, reduce system losses, and ultimately decrease power costs. Improving system power factor can reduce reactive and active power losses for both industry and utilities through the addition of shunt capacitors. This Guide Book gives electric utility technical staff, industrial end-users, consultants and BPA employees a step-by-step method for evaluating the cost effectiveness of installing power factor correction capacitors in an industrial plant.

  4. Sexual harassment: identifying risk factors.

    PubMed

    O'Hare, E A; O'Donohue, W

    1998-12-01

    A new model of the etiology of sexual harassment, the four-factor model, is presented and compared with several models of sexual harassment including the biological model, the organizational model, the sociocultural model, and the sex role spillover model. A number of risk factors associated with sexually harassing behavior are examined within the framework of the four-factor model of sexual harassment. These include characteristics of the work environment (e.g., sexist attitudes among co-workers, unprofessional work environment, skewed sex ratios in the workplace, knowledge of grievance procedures for sexual harassment incidents) as well as personal characteristics of the subject (e.g., physical attractiveness, job status, sex-role). Subjects were 266 university female faculty, staff, and students who completed the Sexual Experience Questionnaire to assess the experience of sexual harassment and a questionnaire designed to assess the risk factors stated above. Results indicated that the four-factor model is a better predictor of sexual harassment than the alternative models. The risk factors most strongly associated with sexual harassment were an unprofessional environment in the workplace, sexist atmosphere, and lack of knowledge about the organization's formal grievance procedures.

  5. Interstitial fibrosis and growth factors.

    PubMed Central

    Lasky, J A; Brody, A R

    2000-01-01

    Interstitial pulmonary fibrosis (IPF) is scarring of the lung caused by a variety of inhaled agents including mineral particles, organic dusts, and oxidant gases. The disease afflicts millions of individuals worldwide, and there are no effective therapeutic approaches. A major reason for this lack of useful treatments is that few of the molecular mechanisms of disease have been defined sufficiently to design appropriate targets for therapy. Our laboratory has focused on the molecular mechanisms through which three selected peptide growth factors could play a role in the development of IPF. Hundreds of growth factors and cytokines could be involved in the complex disease process. We are studying platelet-derived growth factor because it is the most potent mesenchymal cell mitogen yet described, transforming growth factor beta because it is a powerful inducer of extracellular matrix (scar tissue) components by mesenchymal cells, and tumor necrosis factor alpha because it is a pleiotropic cytokine that we and others have shown is essential for the development of IPF in animal models. This review describes some of the evidence from studies in humans, in animal models, and in vitro, that supports the growth factor hypothesis. The use of modern molecular and transgenic technologies could elucidate those targets that will allow effective therapeutic approaches. Images Figure 1 Figure 2 PMID:10931794

  6. [Neuronal growth factors--neurotrophins].

    PubMed

    Meyer, M; Rasmussen, J Z

    1999-04-05

    Neurotrophic factors are polypeptides primarily known to regulate the survival and differentiation of nerve cells during the development of the peripheral and central nervous systems. The neurotrophic factors act via specific receptors after retrograde axonal transport from the nerve fibre target areas back to the cell bodies, and locally through autocrine and paracrine mechanisms linked to nerve cell activity. In the mature nervous system, neurotrophic factors maintain morphological and neurochemical characteristics of nerve cells and promote activity-dependent dynamic/plastic changes in the synaptic contacts between nerve cells by strengthening functionally active synaptic connections. Induction and increased production of neurotrophic factors in relation to neural injuries are thought to serve protective and reparative purposes. Specific neurotrophic factors have thus been shown to protect nerve cells in a number of experimental models for neurodegenerative diseases, such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis, just as specific neurotrophic factors have been shown to stimulate regenerative growth of both peripheral and central nerve fibres. Today, problems with continuous and localized delivery of specific neurotrophins or combinations thereof into the nervous system appear to be the most important obstacle for more widespread clinical application.

  7. Post-mortem pathologic and genetic studies in "dead in bed syndrome" cases in type 1 diabetes mellitus.

    PubMed

    Tu, Emily; Bagnall, Richard D; Duflou, Johan; Lynch, Matthew; Twigg, Stephen M; Semsarian, Christopher

    2010-03-01

    Dead in bed syndrome is a poorly understood cause of sudden death in young people with type 1 diabetes. The underlying cause remains unknown. One possible explanation may involve prolongation of the QT interval followed by a terminal malignant arrhythmia. Risk factors associated with QT interval prolongation include hypoglycemia and cardiac autonomic neuropathy. We sought to identify myocardial cellular changes and genetic influences that may contribute to the pathogenesis of dead in bed syndrome. Post-mortem reports between 1994 and 2006 from the 2 largest Departments of Forensic Medicine in Australia were reviewed for dead in bed syndrome cases. Post-mortem heart sections were immunohistochemically stained for collagen types I and III and connective tissue growth factor (CTGF). Genomic DNA was prepared from post-mortem samples, and genetic analysis was performed in the SCN5A, G6PC, PHOX2B, and CTGF genes. Twenty-two dead in bed syndrome cases were identified and staining of heart sections for collagen I and III, and CTGF showed no differences between dead in bed syndrome cases and controls. Genetic screening of SCN5A revealed 3 silent polymorphisms A29A, E1061E, and D1819D and 1 protein-changing variant H558R. No genetic variants were found in G6PC, PHOX2B, and CTGF, and dead in bed syndrome cases were not associated with the G-945C CTGF promoter polymorphism. In conclusion, this study is the first to investigate potential pathogenic mechanisms underlying the dead in bed syndrome in type 1 diabetes with the results substantially adding to knowledge of this condition. Understanding the causes and triggers of dead in bed syndrome will be critical in facilitating the identification of patients with type 1 diabetes at highest risk of developing sudden death.

  8. Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep.

    PubMed

    Lee, Chang H; Rodeo, Scott A; Fortier, Lisa Ann; Lu, Chuanyong; Erisken, Cevat; Mao, Jeremy J

    2014-12-10

    Regeneration of complex tissues, such as kidney, liver, and cartilage, continues to be a scientific and translational challenge. Survival of ex vivo cultured, transplanted cells in tissue grafts is among one of the key barriers. Meniscus is a complex tissue consisting of collagen fibers and proteoglycans with gradient phenotypes of fibrocartilage and functions to provide congruence of the knee joint, without which the patient is likely to develop arthritis. Endogenous stem/progenitor cells regenerated the knee meniscus upon spatially released human connective tissue growth factor (CTGF) and transforming growth factor-β3 (TGFβ3) from a three-dimensional (3D)-printed biomaterial, enabling functional knee recovery. Sequentially applied CTGF and TGFβ3 were necessary and sufficient to propel mesenchymal stem/progenitor cells, as a heterogeneous population or as single-cell progenies, into fibrochondrocytes that concurrently synthesized procollagens I and IIα. When released from microchannels of 3D-printed, human meniscus scaffolds, CTGF and TGFβ3 induced endogenous stem/progenitor cells to differentiate and synthesize zone-specific type I and II collagens. We then replaced sheep meniscus with anatomically correct, 3D-printed scaffolds that incorporated spatially delivered CTGF and TGFβ3. Endogenous cells regenerated the meniscus with zone-specific matrix phenotypes: primarily type I collagen in the outer zone, and type II collagen in the inner zone, reminiscent of the native meniscus. Spatiotemporally delivered CTGF and TGFβ3 also restored inhomogeneous mechanical properties in the regenerated sheep meniscus. Survival and directed differentiation of endogenous cells in a tissue defect may have implications in the regeneration of complex (heterogeneous) tissues and organs.

  9. Immunocytochemical traits of type IV fibrocytes and their possible relations to cochlear function and pathology.

    PubMed

    Adams, Joe C

    2009-09-01

    One of the more consistent and least understood changes in the aging human cochlea is the progressive loss of fibrocytes within the spiral ligament. This report presents an animal model for type IV fibrocyte loss, along with immunocytochemical evidence that noise-induced loss of these cells may account for previously unexplained hearing losses. The remarkably low threshold for noise-induced loss of type IV fibrocytes, approximately 24 dB less than the threshold for adjacent hair cell destruction, may account for the prevalence of missing fibrocytes in humans. In mice, changes in the spectrum of traumatizing noise had little effect upon the site of loss of the fibrocytes, suggesting that the primary site of damage that induced the loss was the basal-most cochlear turn, a site expected to be damaged by all three noise bands. Type IV fibrocytes were found to immunostain for connective tissue growth factor (CTGF) and for transforming growth factor beta receptor 3, a receptor that is known to activate CTGF expression. Type IV fibrocytes lack immunostaining for adenosine triphosphatase and connexins that are key players in potassium ion uptake and transmission, which suggests that they play little, if any, role in potassium recycling from perilymphatic space to the endolymphatic space. Consequently, their loss probably does not directly reduce this process. Immunostaining for a receptor for CTGF, low-density-lipoprotein-related protein 1, indicated that CTGF acts as an autocrine and a paracrine agent within the cochlea. The lack of CTGF paracrine effects following noise-induced loss of type IV fibrocytes may account for previously unexplained hearing losses.

  10. Extracellular Matrix-Mediated Differentiation of Periodontal Progenitor Cells

    PubMed Central

    Dangaria, Smit J.; Ito, Yoshihiro; Walker, Cameron; Druzinsky, Robert; Luan, Xianghong; Diekwisch, Thomas G.H.

    2009-01-01

    The periodontal ligament (PDL) is a specialized connective tissue that connects the surface of the tooth root with the bony tooth socket. The healthy PDL harbors stem cell niches and extracellular matrix (ECM) microenvironments that facilitate periodontal regeneration. During periodontal disease, the PDL is often compromised or destroyed, reducing the life-span of the tooth. In order to explore new approaches toward the regeneration of diseased periodontal tissues, we have tested the effect of periodontal ECM signals, fibroblast growth factor 2 (FGF2), connective tissue growth factor (CTGF), and the cell adhesion peptide Arg-Gly- Asp (RGD) on the differentiation of two types of periodontal progenitor cells, PDL progenitor cells (PDLPs) and dental follicle progenitor cells (DFCs). Our studies documented that CTGF and FGF2 significantly enhanced the expression of collagens I & III, biglycan and periostin in tissue engineered regenerates after 4 weeks compared to untreated controls. Specifically, CTGF promoted mature PDL-like tissue regeneration as demonstrated by dense periostin localization in collagen fiber bundles. CTGF and FGF2 displayed synergistic effects on collagen III and biglycan gene expression, while effects on mineralization were antagonistic to each other: CTGF promoted while FGF2 inhibited mineralization in PDL cell cultures. Incorporation of RGD peptides in hydrogel matrices significantly enhanced attachment, spreading, survival and mineralization of the encapsulated DFCs, suggesting that RGD additives might promote the use of hydrogels for periodontal mineralized tissue engineering. Together, our studies have documented the effect of three key components of the periodontal ECM on the differentiation of periodontal progenitor populations. PMID:19433344

  11. Factors influencing healthcare service quality

    PubMed Central

    Mosadeghrad, Ali Mohammad

    2014-01-01

    Background: The main purpose of this study was to identify factors that influence healthcare quality in the Iranian context. Methods: Exploratory in-depth individual and focus group interviews were conducted with 222 healthcare stakeholders including healthcare providers, managers, policy-makers, and payers to identify factors affecting the quality of healthcare services provided in Iranian healthcare organisations. Results: Quality in healthcare is a production of cooperation between the patient and the healthcare provider in a supportive environment. Personal factors of the provider and the patient, and factors pertaining to the healthcare organisation, healthcare system, and the broader environment affect healthcare service quality. Healthcare quality can be improved by supportive visionary leadership, proper planning, education and training, availability of resources, effective management of resources, employees and processes, and collaboration and cooperation among providers. Conclusion: This article contributes to healthcare theory and practice by developing a conceptual framework that provides policy-makers and managers a practical understanding of factors that affect healthcare service quality. PMID:25114946

  12. Elongation factors in protein synthesis.

    PubMed

    Kraal, B; Bosch, L; Mesters, J R; de Graaf, J M; Woudt, L P; Vijgenboom, E; Heinstra, P W; Zeef, L A; Boon, C

    1993-01-01

    Recent discoveries of elongation factor-related proteins have considerably complicated the simple textbook scheme of the peptide chain elongation cycle. During growth and differentiation the cycle may be regulated not only by factor modification but also factor replacement. In addition, rare tRNAs may have their own rare factor proteins. A special case is the acquisition of resistance by bacteria to elongation factor-directed antibiotics. Pertinent data from the literature and our own work with Escherichia coli and Streptomyces are discussed. The GTP-binding domain of EF-Tu has been studied extensively, but little molecular detail is available on the interactions with its other ligands or effectors, or on the way they are affected by the GTPase switch signal. A growing number of EF-Tu mutants obtained by ourselves and others are helping us in testing current ideas. We have found a synergistic effect between EF-Tu and EF-G in their uncoupled GTPase reactions on empty ribosomes. Only the EF-G reaction is perturbed by fluoroaluminates.

  13. Geomorphological factors of flash floods

    NASA Astrophysics Data System (ADS)

    Kuznetsova, Yulia

    2016-04-01

    Growing anthropogenic load, rise of extreme meteorological events frequency and total precipitation depth often lead to increasing danger of catastrophic fluvial processes worldwide. Flash floods are one of the most dangerous and less understood types of them. Difficulties of their study are mainly related to short duration of single events, remoteness and hard access to origin areas. Most detailed researches of flash floods focus on hydrological parameters of the flow itself and its meteorological factors. At the same time, importance of the basin geological and geomorphological structure for flash floods generation and the role they play in global sediment redistribution is yet poorly understood. However, understanding and quantitative assessment of these features is a real basis for a complete concept of factors, characteristics and dynamics of flash floods. This work is a review of published data on flash floods, and focuses on the geomorphological factors of the phenomenon. We consider both individual roles and interactions between different geomorphological features (the whole basin parameters, characteristics of the single slopes and valley bottom). Special attention is paid to critical values of certain factors. This approach also highlights the gaps or less studied factors of flash floods. Finally, all data is organized into a complex diagram that may be used for flash floods modeling. This also may help to reach a new level of flash flood predictions and risk assessment.

  14. Derived Basic Ability Factors: A Factor Analysis Replication Study.

    ERIC Educational Resources Information Center

    Lee, Mickey, M.; Lee, Lynda Newby

    The purpose of this study was to replicate the study conducted by Potter, Sagraves, and McDonald to determine whether their recommended analysis could separate criterion variables into similar factors that were stable from year to year and from school to school. The replication samples consisted of all students attending Louisiana State University…

  15. Environmental risk factors for osteoporosis

    SciTech Connect

    Goyer, R.A.; Korach, K.S. ); Epstein, S. ); Bhattacharyya, M. ); Pounds, J. )

    1994-04-01

    Environmental risk factors for osteoporosis were reviewed at a conference held at the National Institute for Environmental Health Sciences 8-9 November 1993. The conference was co-sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Disease and the NIH Office of Research in Women's Health. The objective of the conference was to review what is known about risk factors for osteoporosis and to identify gaps in the present state of knowledge that might be addressed by future research. The conference was divided into two broad themes. The first session focused on current knowledge regarding etiology, risk factors, and approaches to clinical and laboratory diagnosis. This was followed by three sessions in which various environmental pollutants were discussed. Topics selected for review included environmental agents that interfere with bone and calcium metabolism, such as the toxic metals lead, cadmium, aluminum, and fluoride, natural and antiestrogens, calcium, and vitamin D.

  16. [Bifidogenic factors as drug preparations].

    PubMed

    Murashova, A O; Lisitsin, O B; Abramov, N A

    1999-01-01

    The review of new data on the study of bifidobacterial factors of different origin and the probable mechanisms of their favorable action on the microflora of the intestinal tract if presented. The main emphasis is made on the analysis of data on the use of oligosaccharides, including fructo-oligosaccharides, as compounds stimulating the growth and development of bifidobacteria both in pure cultures and in intestinal microflora. Methods for the treatment of natural compounds with a view to enhancing their bifidogenic effect are presented. The possibilities and/or advantages of using bifidogenic factors in vivo and in vitro as medicinal preparations either alone or incorporated in probiotic compositions are evaluated. Suggestion has been made that the choice of the method for using bifidogenic factors may depend on the kind and severity of disturbances in indigenous microflora.

  17. [Success factors in hospital management].

    PubMed

    Heberer, M

    1998-12-01

    The hospital environment of most Western countries is currently undergoing dramatic changes. Competition among hospitals is increasing, and economic issues have become decisive factors for the allocation of medical care. Hospitals therefore require management tools to respond to these changes adequately. The balanced scorecard is a method of enabling development and implementation of a business strategy that equally respects the financial requirements, the needs of the customers, process development, and organizational learning. This method was used to derive generally valid success factors for hospital management based on an analysis of an academic hospital in Switzerland. Strategic management, the focus of medical services, customer orientation, and integration of professional groups across the hospital value chain were identified as success factors for hospital management.

  18. Efficiency factors in Mie scattering

    NASA Astrophysics Data System (ADS)

    Nussenzveig, H. M.; Wiscombe, W. J.

    1980-11-01

    Asymptotic approximations to the Mie efficiency factors for extinction, absorption and radiation pressure are obtained and compared with the exact results. The approximations are derived from the complex-angular-momentum theory of Mie scattering and averaged oxygen ranges of the size parameter (the product of the wave number and the droplet radius) of approximately pi. The accuracy of the approximation with respect to the exact results is found to increase with increasing values of the size parameter and the real component of the refractive index, resulting in relative errors from 1-10% at a size parameter of 10 and from 0.01-0.001% at a size factor of 1000. Computing time with respect to exact computations is also found to be reduced by a factor on the order of the size parameter. It is thus concluded that the Mie formula can advantageously be replaced by the asymptotic ones in most applications.

  19. Factor H and Neisserial pathogenesis

    PubMed Central

    Welsch, Jo Anne; Ram, Sanjay

    2009-01-01

    Both Neisseria gonorrhoeae and N. meningitidis bind to factor H which enhances their ability to evade complement dependent killing. While porin is the ligand for human fH on gonococci, meningococci use a lipoprotein called factor H binding protein (fHbp) to bind to factor H and enhance their ability to evade complement dependent killing. This protein is currently being intensively investigated as a meningococcal vaccine candidate antigen. Consistent with the observation that meningococci cause natural infection only in humans, the organism resists human complement, and are more readily killed by complement from lower animals. This human species-specific complement evasion has important implications for evaluation of vaccine-elicited antibodies using non-human complement sources and development of animal models of disease. PMID:19388163

  20. Factor models for cancer signatures

    NASA Astrophysics Data System (ADS)

    Kakushadze, Zura; Yu, Willie

    2016-11-01

    We present a novel method for extracting cancer signatures by applying statistical risk models (http://ssrn.com/abstract=2732453) from quantitative finance to cancer genome data. Using 1389 whole genome sequenced samples from 14 cancers, we identify an "overall" mode of somatic mutational noise. We give a prescription for factoring out this noise and source code for fixing the number of signatures. We apply nonnegative matrix factorization (NMF) to genome data aggregated by cancer subtype and filtered using our method. The resultant signatures have substantially lower variability than those from unfiltered data. Also, the computational cost of signature extraction is cut by about a factor of 10. We find 3 novel cancer signatures, including a liver cancer dominant signature (96% contribution) and a renal cell carcinoma signature (70% contribution). Our method accelerates finding new cancer signatures and improves their overall stability. Reciprocally, the methods for extracting cancer signatures could have interesting applications in quantitative finance.

  1. Impact beyond the impact factor.

    PubMed

    Zupanc, Günther K H

    2014-02-01

    The journal impact factor is an annually calculated number for each scientific journal, based on the average number of times its articles published in the two preceding years have been cited. It was originally devised as a tool for librarians and publishers to provide information about the citation performance of a journal as a whole, but over the last few decades it has increasingly been used to assess the quality of specific articles and the research performance of individual investigators, institutions, and countries. In addition to this clear abuse of the journal impact factor, several conceptual and technical issues limit its usability as a measure of journal reputation, especially when journals are compared across different fields. An author's decision regarding the suitability of a scholarly journal for publication should, therefore, be based on the impact that this journal makes in the field of research, rather than on the journal impact factor.

  2. Inhibition of Hageman factor activation

    PubMed Central

    Nossel, H. L.; Rubin, H.; Drillings, M.; Hsieh, R.

    1968-01-01

    A method for studying inhibitors of the contact stages of blood coagulation is described. A number of positively charged substances were shown to inhibit the contact stages. The inhibitory substances include spermine, cytochrome c, ribonuclease, and lysozyme. The inhibitory effect of these substances was neutralized by the addition of an activated plasma thromboplastin antecedent, factor XI, (PTA) fraction. Other positively charged substances including protamine, hexadimethrine, polylysine, polyornithine, methylene blue, and ortho-toluidine blue also inhibited the contact stages of coagulation, but the inhibitory effect on coagulation was not neutralized by the activated PTA fraction. Negatively charged substances such as heparin and insulin did not inhibit the contact stages of coagulation. Cytochrome c inhibited Celite adsorption of a partially purified Hageman factor fraction, and cytochrome, ribonuclease, spermine, and lysozome inhibited the adsorption of Hageman factor from PTA-deficient plasma. Very much smaller quantities of Celite completely adsorbed Hageman factor from the fraction rather than from whole plasma, which suggested the possibility that plasma contains an inhibitor or inhibitors of Hageman factor adsorption. Furthermore cytochrome c, spermine, ribonuclease, and lysozyme inhibited the coagulant activity of the following activators of the Hageman and PTA factors: Celite, kaolin, sodium stearate, ellagic acid, and skin. It is suggested that negatively charged sites on these activators are critical for adsorption and activation and that inhibition results from neutralization of the negatively charged sites by the adsorbed inhibtor. Tests with polylysine polymers indicate that inhibitory activity is directly related to molecular size over the molecular weight range of 4000 to 100,000. PMID:5645860

  3. Risk factors for Down syndrome.

    PubMed

    Coppedè, Fabio

    2016-12-01

    Down syndrome (DS) originates, in most of the cases (95 %), from a full trisomy of chromosome 21. The remaining cases are due to either mosaicism for chromosome 21 or the inheritance of a structural rearrangement leading to partial trisomy of the majority of its content. Full trisomy 21 and mosaicism are not inherited, but originate from errors in cell divisions during the development of the egg, sperm or embryo. In addition, full trisomy for chromosome 21 should be further divided into cases of maternal origin, the majority, and cases of paternal origin, less than 10 %. Among cases of maternal origin, a further stratification should be performed into errors that have occurred or originated during the first meiotic division in the maternal grandmother's body and errors that occurred later in life during the second maternal meiotic division. This complex scenario suggests that our understanding of the risk factors for trisomy 21 should take into account the above stratification as it reflects different individuals and generations in which the first error has occurred. Unfortunately, most of the available literature is focused on maternal risk factors, and the only certain risk factors for the birth of a child with DS are advanced maternal age at conception and recombination errors, even though the molecular mechanisms leading to chromosome 21 nondisjunction are still a matter of debate. This article critically reviews the hypotheses and the risk factors which have been suggested to contribute to the birth of a child with DS, including folate metabolism, dietary, lifestyle, environmental, occupational, genetic and epigenetic factors, with focus on maternal and paternal risk factors, and taking into account the possible contribution of the maternal grandmother and that of the developing trisomic embryo, in a complex scenario depicting the birth of a child with DS as the result of complex gene-environment interactions and selection processes involving different

  4. Environmental factors associated with asthma.

    PubMed Central

    Walker, Bailus; Stokes, Lynette D.; Warren, Rueben

    2003-01-01

    Asthma, a disease of attacks and remission, continues to account for substantial morbidity and direct economic costs. Numerous studies--epidemiologic, toxicologic and clinical--present evidence for a broad spectrum of environmental risk factors associated with asthma. This review summarizes current thinking on a subset of these factors. Knowledge of potential environmental determinants of asthma is important to both the patient and healthcare professional in the application of multiple modalities of medical and environmental intervention for management of the development, and exacerbation of this chronic inflammatory disorder of the airways. PMID:12760611

  5. Bayes factors and multimodel inference

    USGS Publications Warehouse

    Link, W.A.; Barker, R.J.; Thomson, David L.; Cooch, Evan G.; Conroy, Michael J.

    2009-01-01

    Multimodel inference has two main themes: model selection, and model averaging. Model averaging is a means of making inference conditional on a model set, rather than on a selected model, allowing formal recognition of the uncertainty associated with model choice. The Bayesian paradigm provides a natural framework for model averaging, and provides a context for evaluation of the commonly used AIC weights. We review Bayesian multimodel inference, noting the importance of Bayes factors. Noting the sensitivity of Bayes factors to the choice of priors on parameters, we define and propose nonpreferential priors as offering a reasonable standard for objective multimodel inference.

  6. Risk Factors in Adolescent Hypertension

    PubMed Central

    Ewald, D. Rose; Haldeman, Lauren A.

    2016-01-01

    Hypertension is a complex and multifaceted disease, with many contributing factors. While diet and nutrition are important influences, the confounding effects of overweight and obesity, metabolic and genetic factors, racial and ethnic predispositions, socioeconomic status, cultural influences, growth rate, and pubertal stage have even more influence and make diagnosis quite challenging. The prevalence of hypertension in adolescents far exceeds the numbers who have been diagnosed; studies have found that 75% or more go undiagnosed. This literature review summarizes the challenges of blood pressure classification in adolescents, discusses the impact of these confounding influences, and identifies actions that will improve diagnosis and treatment outcomes. PMID:27335997

  7. Campylobacter virulence and survival factors.

    PubMed

    Bolton, Declan J

    2015-06-01

    Despite over 30 years of research, campylobacteriosis is the most prevalent foodborne bacterial infection in many countries including in the European Union and the United States of America. However, relatively little is known about the virulence factors in Campylobacter or how an apparently fragile organism can survive in the food chain, often with enhanced pathogenicity. This review collates information on the virulence and survival determinants including motility, chemotaxis, adhesion, invasion, multidrug resistance, bile resistance and stress response factors. It discusses their function in transition through the food processing environment and human infection. In doing so it provides a fundamental understanding of Campylobacter, critical for improved diagnosis, surveillance and control.

  8. Causal Indicators Can Help to Interpret Factors

    ERIC Educational Resources Information Center

    Bentler, Peter M.

    2016-01-01

    The latent factor in a causal indicator model is no more than the latent factor of the factor part of the model. However, if the causal indicator variables are well-understood and help to improve the prediction of individuals' factor scores, they can help to interpret the meaning of the latent factor. Aguirre-Urreta, Rönkkö, and Marakas (2016)…

  9. 48 CFR 2015.304 - Evaluation factors.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false Evaluation factors. 2015... Evaluation factors. The evaluation factors included in the solicitation serve as the standard against which... factors and subfactors by assigning a numerical weight to each factor. If a solicitation uses...

  10. Heredity Factors in Spatial Visualization.

    ERIC Educational Resources Information Center

    Vandenberg, S. G.

    Spatial visualization is not yet clearly understood. Some researchers have concluded that two factors or abilities are involved, spatial orientation and spatial visualization. Different definitions and different tests have been proposed for these two abilities. Several studies indicate that women generally perform more poorly on spatial tests than…

  11. Factors Affecting Willingness to Mentor

    ERIC Educational Resources Information Center

    Ghislieri, Chiara; Gatti, Paola; Quaglino, Gian Piero

    2009-01-01

    The paper presents a survey among 300 employees in Northern Italy to assess the willingness to mentor and identify the factors that affect it. Men and respondents with previous mentoring experience indicate a higher willingness to be a mentor. Willingness is affected by personal characteristics that are perceived as necessary for a mentor and the…

  12. Transcription factor-based biosensor

    DOEpatents

    Dietrich, Jeffrey A; Keasling, Jay D

    2013-10-08

    The present invention provides for a system comprising a BmoR transcription factor, a .sigma..sup.54-RNA polymerase, and a pBMO promoter operatively linked to a reporter gene, wherein the pBMO promoter is capable of expression of the reporter gene with an activated form of the BmoR and the .sigma..sup.54-RNA polymerase.

  13. Five Describing Factors of Dyslexia

    ERIC Educational Resources Information Center

    Tamboer, Peter; Vorst, Harrie C. M.; Oort, Frans J.

    2016-01-01

    Two subtypes of dyslexia (phonological, visual) have been under debate in various studies. However, the number of symptoms of dyslexia described in the literature exceeds the number of subtypes, and underlying relations remain unclear. We investigated underlying cognitive features of dyslexia with exploratory and confirmatory factor analyses. A…

  14. Risk factors for persistent diarrhoea.

    PubMed

    Shahid, N S; Sack, D A; Rahman, M; Alam, A N; Rahman, N

    1988-10-22

    With a systematically sampled population of children aged under 5 attending this centre for diarrhoeal disease research during 1983-5 a retrospective analysis of persistent diarrhoea (defined as greater than 14 days' duration) was performed to identify the possible risk factors for this syndrome. Of the 4155 children included in the analysis, 410 (10%) gave a history of persistent diarrhoea. A comparison with children with acute diarrhoea matched for age showed that 11 factors were correlated with persistent diarrhoea, and strongly associated factors were stools with blood or mucus, or both, lower respiratory tract infection, malnutrition, vitamin A deficiency, and antibiotic use before presentation. The peak age was 2 years, and there was no sex difference. Deaths occurred more often in the group with persistent diarrhoea. Although Shigella spp, Campylobacter jejuni, and Giardia lamblia were frequently identified, their rates of isolation were not significantly higher among patients with persistent diarrhoea. No seasonal variation was observed in the rates of persistent diarrhoea. Although the introduction of family food to the diet was associated with higher rates, this factor was difficult to separate from the age dependent risks.

  15. Factors in Adolescent Rebellious Feelings.

    ERIC Educational Resources Information Center

    Clemens, Patricia W.; Rust, James O.

    1979-01-01

    This study examined 15- and 16-year-old youths' (Midteens') feelings of anomie and rebellion in relation to family and situational factors. Only parents' formal education level and midteens' approval of the way they were being reared correlated significantly with midteens' scores on the Anomia and Rebellion Scales. (Author/SJL)

  16. Family Factors and Student Outcomes

    ERIC Educational Resources Information Center

    Xia, Nailing

    2009-01-01

    There is considerable debate about the relative importance of family versus school factors in producing academic and nonacademic student outcomes, and whether and how their impacts vary across different student groups. In addition to critically reviewing and synthesizing earlier work, this study extends the literature by (a) using the ECLS-K, a…

  17. Human factors in software development

    SciTech Connect

    Curtis, B.

    1986-01-01

    This book presents an overview of ergonomics/human factors in software development, recent research, and classic papers. Articles are drawn from the following areas of psychological research on programming: cognitive ergonomics, cognitive psychology, and psycholinguistics. Topics examined include: theoretical models of how programmers solve technical problems, the characteristics of programming languages, specification formats in behavioral research and psychological aspects of fault diagnosis.

  18. Factors Influencing College Science Success

    ERIC Educational Resources Information Center

    Tai, Robert H.; Sadler, Philip M.; Mintzes, Joel J.

    2006-01-01

    In this paper, the authors report some of the salient findings of a large-scale, four-year national study, conducted at the Harvard-Smithsonian Center for Astrophysics, entitled "Factors Influencing College Science Success" (FICSS), which surveyed college students who enrolled in first-year biology, chemistry, and physics courses…

  19. Risk factors for persistent diarrhoea.

    PubMed Central

    Shahid, N. S.; Sack, D. A.; Rahman, M.; Alam, A. N.; Rahman, N.

    1988-01-01

    With a systematically sampled population of children aged under 5 attending this centre for diarrhoeal disease research during 1983-5 a retrospective analysis of persistent diarrhoea (defined as greater than 14 days' duration) was performed to identify the possible risk factors for this syndrome. Of the 4155 children included in the analysis, 410 (10%) gave a history of persistent diarrhoea. A comparison with children with acute diarrhoea matched for age showed that 11 factors were correlated with persistent diarrhoea, and strongly associated factors were stools with blood or mucus, or both, lower respiratory tract infection, malnutrition, vitamin A deficiency, and antibiotic use before presentation. The peak age was 2 years, and there was no sex difference. Deaths occurred more often in the group with persistent diarrhoea. Although Shigella spp, Campylobacter jejuni, and Giardia lamblia were frequently identified, their rates of isolation were not significantly higher among patients with persistent diarrhoea. No seasonal variation was observed in the rates of persistent diarrhoea. Although the introduction of family food to the diet was associated with higher rates, this factor was difficult to separate from the age dependent risks. PMID:3142603

  20. Transcription factors in alkaloid biosynthesis.

    PubMed

    Yamada, Yasuyuki; Sato, Fumihiko

    2013-01-01

    Higher plants produce a large variety of low-molecular weight secondary compounds. Among them, nitrogen-containing alkaloids are the most biologically active and are often used pharmaceutically. Whereas alkaloid chemistry has been intensively investigated, alkaloid biosynthesis, including the relevant biosynthetic enzymes, genes and their regulation, and especially transcription factors, is largely unknown, as only a limited number of plant species produce certain types of alkaloids and they are difficult to study. Recently, however, several groups have succeeded in isolating the transcription factors that are involved in the biosynthesis of several types of alkaloids, including bHLH, ERF, and WRKY. Most of them show Jasmonate (JA) responsiveness, which suggests that the JA signaling cascade plays an important role in alkaloid biosynthesis. Here, we summarize the types and functions of transcription factors that have been isolated in alkaloid biosynthesis, and characterize their similarities and differences compared to those in other secondary metabolite pathways, such as phenylpropanoid and terpenoid biosyntheses. The evolution of this biosynthetic pathway and regulatory network, as well as the application of these transcription factors to metabolic engineering, is discussed.

  1. Neurophysiological Factors in Spatial Development.

    ERIC Educational Resources Information Center

    Harris, Lauren Jay

    Some of the major lines of investigation that point to neurophysiological factors in spatial skill are presented. These lines include: the two hemispheres of the brain, recent studies, tachistoscopic studies, morphological differences between the cerebral hemispheres, Geschwind and Levitsky's discovery, cerebral dominance re-examined, sex…

  2. Three phase power factor controller

    NASA Technical Reports Server (NTRS)

    Nola, F. J. (Inventor)

    1984-01-01

    A power control circuit for a three phase induction motor is described. Power factors for the three phases are summed to provide a control signal, and this control signal is particularly filtered and then employed to control the duty cycle of each phase of input power to the motor.

  3. Three phase power factor controller

    NASA Technical Reports Server (NTRS)

    Nola, F. J. (Inventor)

    1980-01-01

    A power control circuit for a three phase induction motor is described. The power factors for the three phases are summed to provide a control signal. This control signal is particularly filtered and then employed to control the duty cycle of each phase of input power to the motor.

  4. Soft Factors Influence College Enrollment

    ERIC Educational Resources Information Center

    Fogg, Neeta P.; Harrington, Paul E.

    2010-01-01

    Evidence about the role that "soft factors" like student engagement and school environment play in influencing whether high school students go on to enroll in college is hard to come by. Over the past two years, the Center for Labor Market Studies (CLMS) of Northeastern University, with support from the Nellie Mae Education Foundation…

  5. Suicidal Adolescents: Factors in Evaluation.

    ERIC Educational Resources Information Center

    Gispert, Maria; And Others

    1985-01-01

    Examined factors (family structure, functioning in school, suicidal risk, depression, and stressful life events) related to suicide attempts in 82 adolescents. Suicide risk correlated with current stress, while depression correlated with life-long and current stress. Results indicated most were depressed, angry, and experienced family disruption,…

  6. NASA Space Human Factors Program

    NASA Technical Reports Server (NTRS)

    1992-01-01

    This booklet briefly and succinctly treats 23 topics of particular interest to the NASA Space Human Factors Program. Most articles are by different authors who are mainly NASA Johnson or NASA Ames personnel. Representative topics covered include mental workload and performance in space, light effects on Circadian rhythms, human sleep, human reasoning, microgravity effects and automation and crew performance.

  7. Factors Affecting Auditory Training Gains.

    ERIC Educational Resources Information Center

    Moreau, Roberta M.

    1980-01-01

    A study was undertaken to determine which of nine variables were most related to success in auditory training, using as Ss 43 students at the National Technical Institute for the Deaf. Findings showed that the single largest contributing factor to postcourse gain was the entering English score. (PHR)

  8. Highly parallel sparse Cholesky factorization

    NASA Technical Reports Server (NTRS)

    Gilbert, John R.; Schreiber, Robert

    1990-01-01

    Several fine grained parallel algorithms were developed and compared to compute the Cholesky factorization of a sparse matrix. The experimental implementations are on the Connection Machine, a distributed memory SIMD machine whose programming model conceptually supplies one processor per data element. In contrast to special purpose algorithms in which the matrix structure conforms to the connection structure of the machine, the focus is on matrices with arbitrary sparsity structure. The most promising algorithm is one whose inner loop performs several dense factorizations simultaneously on a 2-D grid of processors. Virtually any massively parallel dense factorization algorithm can be used as the key subroutine. The sparse code attains execution rates comparable to those of the dense subroutine. Although at present architectural limitations prevent the dense factorization from realizing its potential efficiency, it is concluded that a regular data parallel architecture can be used efficiently to solve arbitrarily structured sparse problems. A performance model is also presented and it is used to analyze the algorithms.

  9. HUMAN PROSTATE CANCER RISK FACTORS

    EPA Science Inventory

    Prostate cancer has the highest prevalence of any non-skin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating an...

  10. Logistical Factors in Teachers' Motivation

    ERIC Educational Resources Information Center

    Daniels, Erika

    2016-01-01

    Research in education and psychology contributes to an understanding of how educators create contexts for learning that encourage intrinsic motivation and increase academic achievement. In this article, the researcher investigated how teachers themselves define effectiveness and identified what factors influence their motivation, both positively…

  11. Cognitive Factors in Academic Achievement.

    ERIC Educational Resources Information Center

    Cuasay, Peter

    1992-01-01

    This review explores the factors of cognitive processing, style, and metacognitive organization as they contribute to academic success. Specific discussions consider aspects of short- and long-term memory, including how these affect learning and academic performance, and the keys to attaining long-term memory capability by involving redundancy,…

  12. 2012 Critical Success Factors Report

    ERIC Educational Resources Information Center

    North Carolina Community College System (NJ1), 2012

    2012-01-01

    The Critical Success Factors Report is the North Carolina Community College System's major accountability document. This annual performance report is based on data compiled from the previous year and serves to inform colleges and the public on the performance of North Carolina's 58 community colleges. In 1993, the State Board of Community Colleges…

  13. 2011 Critical Success Factors Report

    ERIC Educational Resources Information Center

    North Carolina Community College System (NJ1), 2011

    2011-01-01

    The Critical Success Factors Report is the North Carolina Community College System's major accountability document. This annual performance report serves to inform colleges and the public on the performance of North Carolina's 58 community colleges. In 1993, the State Board of Community Colleges began monitoring performance data on specific…

  14. Liver fibrogenesis and metabolic factors.

    PubMed

    Anty, Rodolphe; Lemoine, Maud

    2011-06-01

    Mechanisms of liver fibrosis are complex and varied. Among them, metabolic factors are particularly important in the development of fibrosis associated with nonalcoholic steatohepatitis (NASH). These factors are some of the "multiple parallel hits" responsible for liver damage during NASH. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Major profibrogenic protagonists, such as hepatic stellate cells and Kupffer cells, are activated by insulin resistance, apoptosis and local inflammation. Relations between steatosis, insulin resistance and fibrosis are complex. Initially, simple steatosis may be a way to store deleterious free fatty acid in neutral triglycerides. If the lipid storage threshold is exceeded, steatosis may become associated with lipotoxicity. Similarly, interindividual variations of adipose tissue expandability might explain various phenotypes, ranging from "metabolically obese patients with normal weight" to "metabolically normal morbidly obese patients". The metabolic abnormalities in subcutaneous and visceral adipose tissue are insulin resistance and low-grade inflammation, which are associated with increased release of free fatty acid flux and changes in adipocytokines production such as leptin, adiponectin and interleukin 6. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the endocannabinoid system might have important roles in liver fibrogenesis and are potential therapeutic targets. Finally, with the development of new molecular tools, gut microbiota has been recently identified for its pleiotropic functions, including metabolism regulation. Better knowledge of these mechanisms should lead to new strategies for the treatment of metabolic factors that play a key role in liver injuries.

  15. Time dependent view factor methods

    SciTech Connect

    Kirkpatrick, R.C.

    1998-03-01

    View factors have been used for treating radiation transport between opaque surfaces bounding a transparent medium for several decades. However, in recent years they have been applied to problems involving intense bursts of radiation in enclosed volumes such as in the laser fusion hohlraums. In these problems, several aspects require treatment of time dependence.

  16. Psychological Risk Factors in Headache

    PubMed Central

    Nicholson, Robert A.; Houle, Timothy T.; Rhudy, Jamie L.; Norton, Peter J.

    2008-01-01

    Headache is a chronic disease that occurs with varying frequency and results in varying levels of disability. To date, the majority of research and clinical focus has been on the role of biological factors in headache and headache-related disability. However, reliance on a purely biomedical model of headache does not account for all aspects of headache and associated disability. Using a biopsychosocial framework, the current manuscript expands the view of what factors influence headache by considering the role psychological (i.e., cognitive and affective) factors have in the development, course, and consequences of headache. The manuscript initially reviews evidence showing that neural circuits responsible for cognitive–affective phenomena are highly interconnected with the circuitry responsible for headache pain. The manuscript then reviews the influence cognitions (locus of control and self-efficacy) and negative affect (depression, anxiety, and anger) have on the development of headache attacks, perception of headache pain, adherence to prescribed treatment, headache treatment outcome, and headache-related disability. The manuscript concludes with a discussion of the clinical implications of considering psychological factors when treating headache. PMID:17371358

  17. Residue-based scattering factors.

    PubMed

    Xu, Hongliang

    2016-11-01

    A glob is defined as a group of atoms in the crystal which can be chosen in various ways. Globs themselves can be used as scattering elements in the theory of structure determination, just as atoms are used at present. In this paper, amino-acid residues are chosen to form globs and empirical formulas for residue-based scattering factors have been developed.

  18. Peak compression factor of proteins.

    PubMed

    Gritti, Fabrice; Guiochon, Georges

    2009-08-14

    An experimental protocol is proposed in order to measure with accuracy and precision the band compression factor G(12)(2) of a protein in gradient RPLC. Extra-column contributions to bandwidth and the dependency of both the retention factor and the reduced height equivalent to a theoretical plate (HETP) on the mobile phase composition were taken into account. The band compression factor of a small protein (insulin, MW kDa) was measured on a 2.1mm x 50mm column packed with 1.7 microm C(4)-bonded bridged ethylsiloxane BEH-silica particles, for 1 microL samples of dilute insulin solution (<0.05g/L). A linear gradient profile of acetonitrile (25-28% acetonitrile in water containing 0.1% trifluoroacetic acid) was applied during three different gradient times (5, 12.5, and 20 min). The mobile phase flow rate was set at 0.20 mL/min in order to avoid heat friction effects (maximum column inlet pressure 180 bar). The band compression factor of insulin is defined as the ratio of the experimental space band variance measured under gradient conditions to the reference space band variance, which would be observed if no thermodynamic compression would take place during gradient elution. It was 0.56, 0.71, and 0.76 with gradient times of 5, 12.5, and 20 min, respectively. These factors are 20-30% smaller than the theoretical band compression factors (0.79, 0.89, and 0.93) calculated from an equation derived from the well-known Poppe equation, later extended to any retention models and columns whose HETP depends on the mobile phase composition. This difference is explained in part by the omission in the model of the effect of the pressure gradient on the local retention factor of insulin during gradient elution. A much better agreement is obtained for insulin when this effect is taken into account. For lower molecular weight compounds, the pressure gradient has little effect but the finite retention of acetonitrile causes a distortion of the gradient shape during the migration of

  19. Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep

    PubMed Central

    Lee, Chang H.; Rodeo, Scott A.; Fortier, Lisa Ann; Lu, Chuanyong; Erisken, Cevat

    2015-01-01

    Regeneration of complex tissues, such as kidney, liver, and cartilage, continues to be a scientific and translational challenge. Survival of ex vivo cultured, transplanted cells in tissue grafts is among one of the key barriers. Meniscus is a complex tissue consisting of collagen fibers and proteoglycans with gradient phenotypes of fibrocartilage and functions to provide congruence of the knee joint, without which the patient is likely to develop arthritis. Endogenous stem/progenitor cells regenerated the knee meniscus upon spatially released human connective tissue growth factor (CTGF) and transforming growth factor–β3 (TGFβ3) from a three-dimensional (3D)–printed biomaterial, enabling functional knee recovery. Sequentially applied CTGF and TGFβ3 were necessary and sufficient to propel mesenchymal stem/progenitor cells, as a heterogeneous population or as single-cell progenies, into fibrochondrocytes that concurrently synthesized procollagens I and IIα. When released from microchannels of 3D–printed, human meniscus scaffolds, CTGF and TGFβ3 induced endogenous stem/progenitor cells to differentiate and synthesize zone-specific type I and II collagens. We then replaced sheep meniscus with anatomically correct, 3D–printed scaffolds that incorporated spatially delivered CTGF and TGFβ3. Endogenous cells regenerated the meniscus with zone-specific matrix phenotypes: primarily type I collagen in the outer zone, and type II collagen in the inner zone, reminiscent of the native meniscus. Spatiotemporally delivered CTGF and TGFβ3 also restored inhomogeneous mechanical properties in the regenerated sheep meniscus. Survival and directed differentiation of endogenous cells in a tissue defect may have implications in the regeneration of complex (heterogeneous) tissues and organs. PMID:25504882

  20. Micro-precise spatiotemporal delivery system embedded in 3D printing for complex tissue regeneration.

    PubMed

    Tarafder, Solaiman; Koch, Alia; Jun, Yena; Chou, Conrad; Awadallah, Mary R; Lee, Chang H

    2016-04-25

    Three dimensional (3D) printing has emerged as an efficient tool for tissue engineering and regenerative medicine, given its advantages for constructing custom-designed scaffolds with tunable microstructure/physical properties. Here we developed a micro-precise spatiotemporal delivery system embedded in 3D printed scaffolds. PLGA microspheres (μS) were encapsulated with growth factors (GFs) and then embedded inside PCL microfibers that constitute custom-designed 3D scaffolds. Given the substantial difference in the melting points between PLGA and PCL and their low heat conductivity, μS were able to maintain its original structure while protecting GF's bioactivities. Micro-precise spatial control of multiple GFs was achieved by interchanging dispensing cartridges during a single printing process. Spatially controlled delivery of GFs, with a prolonged release, guided formation of multi-tissue interfaces from bone marrow derived mesenchymal stem/progenitor cells (MSCs). To investigate efficacy of the micro-precise delivery system embedded in 3D printed scaffold, temporomandibular joint (TMJ) disc scaffolds were fabricated with micro-precise spatiotemporal delivery of CTGF and TGFβ3, mimicking native-like multiphase fibrocartilage. In vitro, TMJ disc scaffolds spatially embedded with CTGF/TGFβ3-μS resulted in formation of multiphase fibrocartilaginous tissues from MSCs. In vivo, TMJ disc perforation was performed in rabbits, followed by implantation of CTGF/TGFβ3-μS-embedded scaffolds. After 4 wks, CTGF/TGFβ3-μS embedded scaffolds significantly improved healing of the perforated TMJ disc as compared to the degenerated TMJ disc in the control group with scaffold embedded with empty μS. In addition, CTGF/TGFβ3-μS embedded scaffolds significantly prevented arthritic changes on TMJ condyles. In conclusion, our micro-precise spatiotemporal delivery system embedded in 3D printing may serve as an efficient tool to regenerate complex and inhomogeneous tissues.

  1. Motivating factors among Iranian nurses

    PubMed Central

    Negarandeh, Reza; Dehghan-Nayeri, Nahid; Ghasemi, Elham

    2015-01-01

    Background: One of the most important challenges of Iranian health care system is “quality of care,” and it is assumed that motivated nurses are more ready to provide better care. There are limited studies investigating Iranian nurses’ motivations; however, factors which motivate them have not been studied yet. Identifying the motivating factors enables nurse managers to inspire nurses for continuous quality improvement. The aim of this study was to identify motivating factors for Iranian hospital nurses. Materials and Methods: This is a cross-sectional descriptive study in which 310 nurses working at 14 hospitals of Tehran University of Medical Sciences were selected by proportionate stratified random sampling. Data were collected in 2010 by a researcher-developed questionnaire. Descriptive statistics and independent t-test, analysis of variance, Tukey post-hoc test, Chi-Square and Fisher's exact test were used for statistical analysis by Statistical Package for Social Sciences (SPSS) version 16. Results: The mean score of motivation was 90.53 ± 10.76 (range: 59–121). Four motivating factors including “career development” (22.63 ± 5.66), “job characteristics” (34.29 ± 4), “job authority” (18.48 ± 2.79), and “recognition” (15.12 ± 2.5) were recognized. The least mean of the motivation score, considering the number of items, was 3.23 for career development, while the highest mean was 3.81 for job characteristics. Conclusions: The findings showed that motivation of nurses was at a medium level, which calls for improvement. The factors that have the greatest potential to motivate nurses were identified in this study and they can help managers to achieve the goal of continuous quality improvement. PMID:26257797

  2. Prognostic factors in prostate cancer.

    PubMed

    Braeckman, Johan; Michielsen, Dirk

    2007-01-01

    In the nineteenth century the main goal of medicine was predictive: diagnose the disease and achieve a satisfying prognosis of the patient's chances. Today the effort has shifted to cure the disease. Since the twentieth century, the word prognosis has also been used in nonmedical contexts, for example in corporate finance or elections. The most accurate form of prognosis is achieved statistically. Based on different prognostic factors it should be possible to tell patients how they are expected to do after prostate cancer has been diagnosed and how different treatments may change this outcome. A prognosis is a prediction. The word prognosis comes from the Greek word (see text) and means foreknowing. In the nineteenth century this was the main goal of medicine: diagnose the disease and achieve a satisfying prognosis of the patient's chances. Today the effort has shifted towards seeking a cure. Prognostic factors in (prostate) cancer are defined as "variables that can account for some of the heterogeneity associated with the expected course and outcome of a disease". Bailey defined prognosis as "a reasoned forecast concerning the course, pattern, progression, duration, and end of the disease. Prognostic factors are not only essential to understand the natural history and the course of the disease, but also to predict possible different outcomes of different treatments or perhaps no treatment at all. This is extremely important in a disease like prostate cancer where there is clear evidence that a substantial number of cases discovered by prostate-specific antigen (PSA) testing are unlikely ever to become clinically significant, not to mention mortal. Furthermore, prognostic factors are of paramount importance for correct interpretation of clinical trials and for the construction of future trials. Finally, according to WHO national screening committee criteria for implementing a national screening programme, widely accepted prognostic factors must be defined before

  3. Factors influencing permanent teeth eruption. Part one--general factors.

    PubMed

    Almonaitiene, Ruta; Balciuniene, Irena; Tutkuviene, Janina

    2010-01-01

    Variation in the normal eruption of teeth is a common finding, but significant deviation from established norms should alert the clinician to take some diagnostic procedures in order to evaluate patient health and development. Disturbance in tooth eruption time could be a symptom of general condition or indication of altered physiology and craniofacial development. The aim of this review is to analyze general factors that could influence permanent teeth eruption. The articles from 1965 to 2009 in English related to topic were identified. 84 articles were selected for data collection. Although permanent teeth eruption is under significant genetic control, various general factors such as gender, socioeconomic status, craniofacial morphology, body composition can influence this process. Most significant disturbance in teeth emergence is caused by systemic diseases and syndromes.

  4. Sequential coagulation factor VIIa domain binding to tissue factor

    SciTech Connect

    Oesterlund, Maria; Persson, Egon; Freskgard, Per-Ola . E-mail: msv@ifm.liu.se

    2005-12-02

    Vessel wall tissue factor (TF) is exposed to blood upon vascular damage which enables association with factor VIIa (FVIIa). This leads to initiation of the blood coagulation cascade through localization and allosteric induction of FVIIa procoagulant activity. To examine the docking pathway of the FVIIa-TF complex, various residues in the extracellular part of TF (sTF) that are known to interact with FVIIa were replaced with cysteines labelled with a fluorescent probe. By using stopped-flow fluorescence kinetic measurements in combination with surface plasmon resonance analysis, we studied the association of the resulting sTF variants with FVIIa. We found the docking trajectory to be a sequence of events in which the protease domain of FVIIa initiates contact with sTF. Thereafter, the two proteins are tethered via the first epidermal growth factor-like and finally the {gamma}-carboxyglutamic acid (Gla) domain. The two labelled sTF residues interacting with the protease domain of FVIIa bind or become eventually ordered at different rates, revealing kinetic details pertinent to the allosteric activation of FVIIa by sTF. Moreover, when the Gla domain of FVIIa is removed the difference in the rate of association for the remaining domains is much more pronounced.

  5. [Risk factors and protective factors of the insanities].

    PubMed

    Clément, Jean-Pierre

    2007-12-01

    The Alzheimer's disease (AD) is multifactorial. How to explain this group of very heterogeneous factors? Many of them can be considered as biopsychosocial risk factors. In other words, the risk factors, in link with the physiological functioning and a physiopathology, are difficultly dissociable of contingencies of psychological and/or social nature. The vital lead could be the stress bound to these variables, be it biological or psychosocial. It remains to ask the question of the preventive efficiency of treatments to relieve the impact of the traumatizing events of life that entail a depressive state or a state of posttraumatic stress. The hippocamp has to be the object of a quite particular attention. AD is a disease of the adaptation. This integrative model combines three vulnerabilities: a genetic vulnerability which would be there to dictate the type of lesions, their localization and the age of occurence; a psychobiographic vulnerability corresponding to a personality with inadequate mechanisms of defence, precarious adaptability in front of the adversity, weak impact strength and biography built on events of life during childhood, then during the grown-up life of traumatic nature, with a psychosocial environment insufficiently auxiliary; a neuroendocrinologic vulnerability which would base on a deregulation of the corticotrope axis, acquired during its infantile maturation, hampered by too premature stress. It would lead to a bad biological adaptability in stress later, at the origin of the observable lesions in the insanities.

  6. Factors influencing susceptibility to metals.

    PubMed Central

    Gochfeld, M

    1997-01-01

    Although the long-neglected field of human susceptibility to environmental toxicants is currently receiving renewed attention, there is only scant literature on factors influencing susceptibility to heavy metals. Genetic factors may influence the availability of sulfhydryl-containing compounds such as glutathione and metallothionein, which modify the distribution and toxicity of certain metals. Age and gender play a role in modifying uptake and distribution, although the mechanisms are often obscure. Concurrent exposure to divalent cations may enhance or reduce the toxicity of certain metals through competition for receptor-mediated transport or targets. Increasing use of biomarkers of exposure should greatly increase our understanding of the underlying distribution of susceptibility to various environmental agents. PMID:9255566

  7. Factors Impacting Decommissioning Costs - 13576

    SciTech Connect

    Kim, Karen; McGrath, Richard

    2013-07-01

    The Electric Power Research Institute (EPRI) studied United States experience with decommissioning cost estimates and the factors that impact the actual cost of decommissioning projects. This study gathered available estimated and actual decommissioning costs from eight nuclear power plants in the United States to understand the major components of decommissioning costs. Major costs categories for decommissioning a nuclear power plant are removal costs, radioactive waste costs, staffing costs, and other costs. The technical factors that impact the costs were analyzed based on the plants' decommissioning experiences. Detailed cost breakdowns by major projects and other cost categories from actual power plant decommissioning experiences will be presented. Such information will be useful in planning future decommissioning and designing new plants. (authors)

  8. Nutritional Factors Affecting Mental Health

    PubMed Central

    Lim, So Young; Kim, Eun Jin; Kim, Arang; Lee, Hee Jae; Choi, Hyun Jin

    2016-01-01

    Dietary intake and nutritional status of individuals are important factors affecting mental health and the development of psychiatric disorders. Majority of scientific evidence relating to mental health focuses on depression, cognitive function, and dementia, and limited evidence is available about other psychiatric disorders including schizophrenia. As life span of human being is increasing, the more the prevalence of mental disorders is, the more attention rises. Lists of suggested nutritional components that may be beneficial for mental health are omega-3 fatty acids, phospholipids, cholesterol, niacin, folate, vitamin B6, and vitamin B12. Saturated fat and simple sugar are considered detrimental to cognitive function. Evidence on the effect of cholesterol is conflicting; however, in general, blood cholesterol levels are negatively associated with the risk of depression. Collectively, the aims of this review are to introduce known nutritional factors for mental health, and to discuss recent issues of the nutritional impact on cognitive function and healthy brain aging. PMID:27482518

  9. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  10. Human factors in contingency operations.

    PubMed

    Mercer, Simon J; Khan, M A; Scott, T; Matthews, J J; Henning, Dcw; Stapley, S

    2016-06-10

    The UK Defence Medical Services are currently supporting contingency operations following a period of intensive activity in relatively mature trauma systems in Iraq and Afghanistan. Among the key lessons identified, human factors or non-technical skills played an important role in the improvement of patient care. This article describes the importance of human factors on Role 2 Afloat, one of the Royal Navy's maritime contingency capabilities, and illustrates how they are vital to ensuring that correct decisions are made for patient care in a timely manner. Teamwork and communication are particularly important to ensure that limited resources such as blood products and other consumables are best used and that patients are evacuated promptly, allowing the facility to accept further casualties and therefore maintain operational capability. These ideas may be transferred to any small specialist team given a particular role to perform.

  11. Factors influencing pacing in triathlon.

    PubMed

    Wu, Sam Sx; Peiffer, Jeremiah J; Brisswalter, Jeanick; Nosaka, Kazunori; Abbiss, Chris R

    2014-01-01

    Triathlon is a multisport event consisting of sequential swim, cycle, and run disciplines performed over a variety of distances. This complex and unique sport requires athletes to appropriately distribute their speed or energy expenditure (ie, pacing) within each discipline as well as over the entire event. As with most physical activity, the regulation of pacing in triathlon may be influenced by a multitude of intrinsic and extrinsic factors. The majority of current research focuses mainly on the Olympic distance, whilst much less literature is available on other triathlon distances such as the sprint, half-Ironman, and Ironman distances. Furthermore, little is understood regarding the specific physiological, environmental, and interdisciplinary effects on pacing. Therefore, this article discusses the pacing strategies observed in triathlon across different distances, and elucidates the possible factors influencing pacing within the three specific disciplines of a triathlon.

  12. Factorization of chiral string amplitudes

    NASA Astrophysics Data System (ADS)

    Huang, Yu-tin; Siegel, Warren; Yuan, Ellis Ye

    2016-09-01

    We re-examine a closed-string model defined by altering the boundary conditions for one handedness of two-dimensional propagators in otherwise-standard string theory. We evaluate the amplitudes using Kawai-Lewellen-Tye factorization into open-string amplitudes. The only modification to standard string theory is effectively that the spacetime Minkowski metric changes overall sign in one open-string factor. This cancels all but a finite number of states: as found in earlier approaches, with enough supersymmetry (e.g., type II) the tree amplitudes reproduce those of the massless truncation of ordinary string theory. However, we now find for the other cases that additional fields, formerly thought to be auxiliary, describe new spin-2 states at the two adjacent mass levels (tachyonic and tardyonic). The tachyon is always a ghost, but can be avoided in the heterotic case.

  13. [Environmental factors in juvenile delinquency].

    PubMed

    Barbagallo, A; Bellia, A; Benvenuto, G; Contiguglia, M A; Cosentino, F

    1975-09-12

    Experimental data are cited for the proposition that the complicated aspects of juvenile delinquency can only be understood and explained by adopting a simultaneous psychological and sociological approach. It is also shown that the manifestations of delinquency, though not its actual presence, may be influenced by sex and a depressed city or rural background. Environmental factors serving as stimulating features and hereditary (i.e. predisposing) factors undoubtedly contribute to the formation of the Ego. The former, however, are elaborated by their receipient and are not sufficient to explain a certain type of behaviour. The influence of cultural models should not be underestimated. These, where predominant, tend to render normative what may be considered as deviant.

  14. Factors contributing to adolescent obesity.

    PubMed

    Al-Kloub, Manal I; Froelicher, Erika S

    2009-06-01

    Obesity in children is a significant public health concern. The prevalence of overweight and obesity in Jordanian children, and adolescents has increased in the last decade. The consequences of obesity to health in childhood and adulthood have both medical, and economic cost to individuals and society. This paper reviews the factors that contribute to adolescent obesity and emphasizes behavioral and environmental factors. An individual's behaviors such as increased consumption of high caloric foods, increased sedentary activity while decreasing physical activity has been identified as key issues in the development of obesity. Additionally, the current environment in homes, schools, and neighborhoods tend to discourage a healthy lifestyle. A comprehensive approach that involves the whole community is the best strategy for preventing adolescent obesity. Nurses are in a unique position to provide leadership in developing programs for healthier lifestyle choices for adolescents' and adoption of these goals into their daily lives.

  15. Factors influencing pacing in triathlon

    PubMed Central

    Wu, Sam SX; Peiffer, Jeremiah J; Brisswalter, Jeanick; Nosaka, Kazunori; Abbiss, Chris R

    2014-01-01

    Triathlon is a multisport event consisting of sequential swim, cycle, and run disciplines performed over a variety of distances. This complex and unique sport requires athletes to appropriately distribute their speed or energy expenditure (ie, pacing) within each discipline as well as over the entire event. As with most physical activity, the regulation of pacing in triathlon may be influenced by a multitude of intrinsic and extrinsic factors. The majority of current research focuses mainly on the Olympic distance, whilst much less literature is available on other triathlon distances such as the sprint, half-Ironman, and Ironman distances. Furthermore, little is understood regarding the specific physiological, environmental, and interdisciplinary effects on pacing. Therefore, this article discusses the pacing strategies observed in triathlon across different distances, and elucidates the possible factors influencing pacing within the three specific disciplines of a triathlon. PMID:25258562

  16. On factorization of molecular wavefunctions

    NASA Astrophysics Data System (ADS)

    Jecko, Thierry; Sutcliffe, Brian T.; Woolley, R. Guy

    2015-11-01

    Recently there has been a renewed interest in the chemical physics literature of factorization of the position representation eigenfunctions Φ of the molecular Schrödinger equation as originally proposed by Hunter in the 1970s. The idea is to represent Φ in the form φχ where χ is purely a function of the nuclear coordinates, while φ must depend on both electron and nuclear position variables in the problem. This is a generalization of the approximate factorization originally proposed by Born and Oppenheimer, the hope being that an ‘exact’ representation of Φ can be achieved in this form with φ and χ interpretable as ‘electronic’ and ‘nuclear’ wavefunctions respectively. We offer a mathematical analysis of these proposals that identifies ambiguities stemming mainly from the singularities in the Coulomb potential energy.

  17. Endometriosis, Angiogenesis and Tissue Factor

    PubMed Central

    Krikun, Graciela

    2012-01-01

    Tissue factor (TF), is a cellular receptor that binds the factor VII/VIIa to initiate the blood coagulation cascade. In addition to its role as the initiator of the hemostatic cascade, TF is known to be involved in angiogenesis via intracellular signaling that utilizes the protease activated receptor-2 (PAR-2). We now review the physiologic expression of TF in the endometrium and its altered expression in multiple cell types derived from eutopic and ectopic endometrium from women with endometriosis compared with normal endometrium. Our findings suggest that TF might be an ideal target for therapeutic intervention in endometriosis. We have employed a novel immunoconjugate molecule known as Icon and were able to eradicate endometrial lesions in a mouse model of endometriosis without affecting fertility. These findings have major implications for potential treatment in humans. PMID:24278684

  18. Graybody Factors and Infrared Divergences

    NASA Astrophysics Data System (ADS)

    Anderson, Paul; Fabbri, Alessandro; Balbinot, Roberto; Parentani, Renaud

    2015-04-01

    A method of computing the gray-body factors for static spherically symmetric and BEC acoustic black holes using a Volterra integral equation is given. The results are used to investigate infrared divergences in the particle number, two-point function, point-split stress-energy tensor and density-density correlation function. Infrared divergences in the particle number and two-point function occur if the gray-body factor approaches a nonzero constant in the zero frequency limit, as happens for Schwarzschild-de Sitter black holes and BEC acoustic black holes. However, no infrared divergences occur in the point-split stress-energy tensor or the density-density correlation function. Supported in part by the National Science Foundation under Grant Nos. PHY-0856050 and PHY-1308325.

  19. [Preeclampsia as cardiovascular risk factor].

    PubMed

    Heida, Karst Y; Franx, Arie; Bots, Michiel L

    2013-01-01

    Cardiovascular diseases (CVD) are the primary cause of death in women. Guidelines for identifying high-risk individuals have been developed, e.g. the Dutch Guideline on Cardiovascular Risk Management. In the most recent version of this guideline, diabetes mellitus (DM) and rheumatoid arthritis (RA) are cited as cardiovascular risk factors; therefore, individuals with these conditions are identified as being at high risk. As with DM and RA, there is strong evidence that the experience of having a hypertensive disorder during pregnancy is a cardiovascular risk factor. This is particularly the case for early preeclampsia, which constitutes a 7-fold increased risk of ischemic heart disease. However, in the Netherlands, there are no guidelines and there is no consensus on how to screen or treat these women. Trial evidence is therefore urgently needed to substantiate the value of cardiovascular risk management for those women with a history of hypertension during pregnancy.

  20. Mixed real/complex factorization

    SciTech Connect

    Lima, L.T.G. . Dept. of Electrical Engineering); Martines, N.; Pinto, H.J.C.P. . Centro de Pesquisas de Energia Electrica)

    1993-02-01

    This paper describes a mixed real/complex sparse matrix factorization and solution scheme applied to a large matrix problem. Large system eigenanalysis and frequency domain methods will directly benefit from the proposed scheme, which can reduce both memory and CPU time requirements when compared to conventional complex-only solutions. The application in hand is the small signal electromechanical stability analysis of large power systems. The savings obtained are significant considering the CPU intensive nature of these matrix problems.

  1. Factor weighting in DRASTIC modeling.

    PubMed

    Pacheco, F A L; Pires, L M G R; Santos, R M B; Sanches Fernandes, L F

    2015-02-01

    Evaluation of aquifer vulnerability comprehends the integration of very diverse data, including soil characteristics (texture), hydrologic settings (recharge), aquifer properties (hydraulic conductivity), environmental parameters (relief), and ground water quality (nitrate contamination). It is therefore a multi-geosphere problem to be handled by a multidisciplinary team. The DRASTIC model remains the most popular technique in use for aquifer vulnerability assessments. The algorithm calculates an intrinsic vulnerability index based on a weighted addition of seven factors. In many studies, the method is subject to adjustments, especially in the factor weights, to meet the particularities of the studied regions. However, adjustments made by different techniques may lead to markedly different vulnerabilities and hence to insecurity in the selection of an appropriate technique. This paper reports the comparison of 5 weighting techniques, an enterprise not attempted before. The studied area comprises 26 aquifer systems located in Portugal. The tested approaches include: the Delphi consensus (original DRASTIC, used as reference), Sensitivity Analysis, Spearman correlations, Logistic Regression and Correspondence Analysis (used as adjustment techniques). In all cases but Sensitivity Analysis, adjustment techniques have privileged the factors representing soil characteristics, hydrologic settings, aquifer properties and environmental parameters, by leveling their weights to ≈4.4, and have subordinated the factors describing the aquifer media by downgrading their weights to ≈1.5. Logistic Regression predicts the highest and Sensitivity Analysis the lowest vulnerabilities. Overall, the vulnerability indices may be separated by a maximum value of 51 points. This represents an uncertainty of 2.5 vulnerability classes, because they are 20 points wide. Given this ambiguity, the selection of a weighting technique to integrate a vulnerability index may require additional

  2. Impact fact-or fiction?

    PubMed Central

    Pulverer, Bernd

    2013-01-01

    The Journal Impact Factor dominates research assessment in many disciplines and in many countries. While research assessment will always have to rely to some extent on quantitative, standardized metrics, the focus on this single measure has gone so far as to hamper and distort scientific research. The Declaration on Research Assessment (DORA), signed by influential journals, funders, academic institutions and individuals across the natural sciences, aims to raise awareness and to redress the use of non-objective research assessment practices. PMID:23685358

  3. Congenital deficiency of factor VII.

    PubMed

    Sikka, M; Gomber, S; Madan, N; Rusia, U; Sharma, S

    1996-01-01

    A case of congenital factor VII deficiency in a five-year-old child is reported. The patient, born of a non-consanguineous marriage, presented with repeated bouts of epistaxis since childhood. The prothrombin time (PT) was markedly prolonged with a normal bleeding time (BT), partial thromboplastin time with Kaolin (PTTK) and platelet count. The patient has been on follow up for the last four years and is doing apparently well.

  4. Human Factors in Space Exploration

    NASA Technical Reports Server (NTRS)

    Jones, Patricia M.; Fiedler, Edna

    2010-01-01

    The exploration of space is one of the most fascinating domains to study from a human factors perspective. Like other complex work domains such as aviation (Pritchett and Kim, 2008), air traffic management (Durso and Manning, 2008), health care (Morrow, North, and Wickens, 2006), homeland security (Cooke and Winner, 2008), and vehicle control (Lee, 2006), space exploration is a large-scale sociotechnical work domain characterized by complexity, dynamism, uncertainty, and risk in real-time operational contexts (Perrow, 1999; Woods et ai, 1994). Nearly the entire gamut of human factors issues - for example, human-automation interaction (Sheridan and Parasuraman, 2006), telerobotics, display and control design (Smith, Bennett, and Stone, 2006), usability, anthropometry (Chaffin, 2008), biomechanics (Marras and Radwin, 2006), safety engineering, emergency operations, maintenance human factors, situation awareness (Tenney and Pew, 2006), crew resource management (Salas et aI., 2006), methods for cognitive work analysis (Bisantz and Roth, 2008) and the like -- are applicable to astronauts, mission control, operational medicine, Space Shuttle manufacturing and assembly operations, and space suit designers as they are in other work domains (e.g., Bloomberg, 2003; Bos et al, 2006; Brooks and Ince, 1992; Casler and Cook, 1999; Jones, 1994; McCurdy et ai, 2006; Neerincx et aI., 2006; Olofinboba and Dorneich, 2005; Patterson, Watts-Perotti and Woods, 1999; Patterson and Woods, 2001; Seagull et ai, 2007; Sierhuis, Clancey and Sims, 2002). The human exploration of space also has unique challenges of particular interest to human factors research and practice. This chapter provides an overview of those issues and reports on sorne of the latest research results as well as the latest challenges still facing the field.

  5. Human factors in incident reporting

    NASA Technical Reports Server (NTRS)

    Jones, S. G.

    1993-01-01

    The paper proposes a cooperative research effort be undertaken by academic institutions and industry organizations toward the compilation of a human factors data base in conjunction with technical information. Team members in any discipline can benefit and learn from observing positive examples of decision making and performance by crews under stressful or less than optimal circumstances. The opportunity to note trends in interpersonal and interactive behaviors and to categorize them is terms of more or less desirable outcomes should not be missed.

  6. Nonproductive Factor Allowance. (Pilot Study).

    DTIC Science & Technology

    1980-03-31

    a separate factor for each size of facility, i.e., MEDCEN, Large MEDDAC, and Small MEDDAC. f. In a GAO audit report, "Development and Use of Military...measurement in determining and Justifying staffing requirements. g. Another GAO audit report, "Uniform Accounting and Workload Measurement Systems Needed for...Effective Writing, AFIT, Survival, TDY, Technical Training, IDEA High School, CDC and Survey Taking. Also taking tests such as PFE , SKT, AF Sup Exam, CLEP

  7. Dietary factors affecting polyphenol bioavailability.

    PubMed

    Bohn, Torsten

    2014-07-01

    While many epidemiological studies have associated the consumption of polyphenols within fruits and vegetables with a decreased risk of developing several chronic diseases, intervention studies have generally not confirmed these beneficial effects. The reasons for this discrepancy are not fully understood but include potential differences in dosing, interaction with the food matrix, and differences in polyphenol bioavailability. In addition to endogenous factors such as microbiota and digestive enzymes, the food matrix can also considerably affect bioaccessibility, uptake, and further metabolism of polyphenols. While dietary fiber (such as hemicellulose), divalent minerals, and viscous and protein-rich meals are likely to cause detrimental effects on polyphenol bioaccessibility, digestible carbohydrates, dietary lipids (especially for hydrophobic polyphenols, e.g., curcumin), and additional antioxidants may enhance polyphenol availability. Following epithelial uptake, polyphenols such as flavonoids may reduce phase II metabolism and excretion, enhancing polyphenol bioavailability. Furthermore, polyphenols may act synergistically due to their influence on efflux transporters such as p-glycoprotein. In order to understand polyphenol bioactivity, increased knowledge of the factors affecting polyphenol bioavailability, including dietary factors, is paramount.

  8. [Nutritional factors in preventing osteoporosis].

    PubMed

    Martín Jiménez, Juan Antonio; Consuegra Moya, Belkis; Martín Jiménez, María Teresa

    2015-07-18

    Osteoporosis, main risk factor for suffering fragility fractures, is an important public health problem which has undoubted social, health and economic impact; but mainly causes pain, functional limitation and severe alterations in the patient's quality of life. Its current prevalence is very high and a further increase is expected due to a higher life expectancy and the progressive ageing of the population. In the prevention of osteoporosis, the main goal is to prevent fragility fractures; for this reason, it is necessary to: 1) promote bone formation in youth, to get sufficient bone mass peak, 2) reduce bone loss in adulthood, especially after menopause, 3) maintain bone health throughout life, and 4) prevent falls. There is enough evidence that multifactorial strategies (assessment of risk factors, healthy lifestyle habits, smoking cessation, moderation in alcohol consumption, physical exercise, outdoor activity with prudent exposure to sunlight, and a varied and balanced diet), are effective in the population at risk. Regarding factors for the prevention of osteoporosis, current recommendations are: increased consumption of calcium, phosphorus, magnesium and fluoride; provide adequate vitamin D (even with fortified food if necessary); consumption of foods rich in omega-3 acids; reduction of salt and prepared ready meals; sufficient but moderate intake of protein and, in the absence of intolerance, promote the consumption of milk and dairy products, especially yogurt and fermented milk products.

  9. Advances of Coagulation Factor XIII

    PubMed Central

    Shi, Da-Yu; Wang, Shu-Jie

    2017-01-01

    Objective: To provide a comprehensive literature review on roles of coagulation factor XIII (FXIII) in coagulation, wound healing, neoplasm, bone metabolism, and pregnancy. Data Sources: All articles in PubMed with key words Coagulation factor XIII, wound, leukemia, tumor, bone, and pregnancy with published date from 2001 to 2016 were included in the study. Frequently cited publications before 2000 were also included. Study Selection: We reviewed the role of FXIII in biologic processes as documented in clinical, animal, and in vitro studies. Results: FXIII, a member of the transglutaminase (TG) family, plays key roles in various biological processes. Besides its well-known function in coagulation, the cross-linking of small molecules catalyzed by FXIII has been found in studies to help promote wound healing, improve bone metabolism, and prevent miscarriages. The study has also shown that FXIII concentration level differs in the blood of patients with leukemia and solid tumors and offers promises as a diagnostic indicator. Conclusions: FXIII has many more biologic functions besides being known as coagulation factor. The TG activity of FXIII contributes to several processes, including wound healing, bone extracellular matrix stabilization, and the interaction between embryo and decidua of uterus. Further research is needed to elucidate the link between FXIII and leukemia and solid tumors. PMID:28091415

  10. [Perception of reproductive risk factors].

    PubMed

    Salinas-Martinez, A M; Martínez-Sanchez, C; Pérez-Segura, J

    1993-01-01

    The objective of this study was to identify risk perception on several factors related to reproductive health, with the goal of implementing an educational intervention based on detected needs. 405 women between 12 and 44 years were interviewed at home. 62.2% perceived the risk of pregnancy at 17 years and younger; 78.8% the risk of pregnancy at 35 years and older; 76.6% the risk of parity of 5 and higher; and 55.1% the risk of birth interval of 2 years and less. 60.5% recognized family history of birth defects, 80.2% age 35 years and older, and 84.4% rubella during pregnancy, as risk factors for newborns with congenital malformations. 27.7% identified history of a low birth weight and 61.0% birth interval of 1 year and less, as risk factors for low birth weight. The majority perceived the risk of tobacco, alcohol and drugs consumption during pregnancy, diseases with no treatment and deficient nutrition. There was an inconsistent influence of social and obstetric variables on risk perception. No linear correlation was detected. Health educators should recognize differences on knowledge and behavior of future receptors before an educational intervention starts.

  11. Human Factors in Financial Trading

    PubMed Central

    Leaver, Meghan; Reader, Tom W.

    2016-01-01

    Objective This study tests the reliability of a system (FINANS) to collect and analyze incident reports in the financial trading domain and is guided by a human factors taxonomy used to describe error in the trading domain. Background Research indicates the utility of applying human factors theory to understand error in finance, yet empirical research is lacking. We report on the development of the first system for capturing and analyzing human factors–related issues in operational trading incidents. Method In the first study, 20 incidents are analyzed by an expert user group against a referent standard to establish the reliability of FINANS. In the second study, 750 incidents are analyzed using distribution, mean, pathway, and associative analysis to describe the data. Results Kappa scores indicate that categories within FINANS can be reliably used to identify and extract data on human factors–related problems underlying trading incidents. Approximately 1% of trades (n = 750) lead to an incident. Slip/lapse (61%), situation awareness (51%), and teamwork (40%) were found to be the most common problems underlying incidents. For the most serious incidents, problems in situation awareness and teamwork were most common. Conclusion We show that (a) experts in the trading domain can reliably and accurately code human factors in incidents, (b) 1% of trades incur error, and (c) poor teamwork skills and situation awareness underpin the most critical incidents. Application This research provides data crucial for ameliorating risk within financial trading organizations, with implications for regulation and policy. PMID:27142394

  12. Factors Affecting Radiologist's PACS Usage.

    PubMed

    Forsberg, Daniel; Rosipko, Beverly; Sunshine, Jeffrey L

    2016-12-01

    The purpose of this study was to determine if any of the factors radiologist, examination category, time of week, and week effect PACS usage, with PACS usage defined as the sequential order of computer commands issued by a radiologist in a PACS during interpretation and dictation. We initially hypothesized that only radiologist and examination category would have significant effects on PACS usage. Command logs covering 8 weeks of PACS usage were analyzed. For each command trace (describing performed activities of an attending radiologist interpreting a single examination), the PACS usage variables number of commands, number of command classes, bigram repetitiveness, and time to read were extracted. Generalized linear models were used to determine the significance of the factors on the PACS usage variables. The statistical results confirmed the initial hypothesis that radiologist and examination category affect PACS usage and that the factors week and time of week to a large extent have no significant effect. As such, this work provides direction for continued efforts to analyze system data to better understand PACS utilization, which in turn can provide input to enable optimal utilization and configuration of corresponding systems. These continued efforts were, in this work, exemplified by a more detailed analysis using PACS usage profiles, which revealed insights directly applicable to improve PACS utilization through modified system configuration.

  13. Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

    SciTech Connect

    Lim, Taekyu; Lee, Inkyoung; Kim, Jungmin; Kang, Won Ki

    2015-10-01

    Purpose: We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Methods and Materials: Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. Results: The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. Conclusion: We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

  14. Academic Success Factors: An IT Student Perspective

    ERIC Educational Resources Information Center

    Zhang, Aimao; Aasheim, Cheryl L.

    2011-01-01

    Numerous studies have identified causal factors for academic success. Factors vary from personal factors, such as cognitive style (McKenzie & Schweitzer, 2001), to social factors, such as culture differences (Aysan, Tanriogen, & Tanriogen, 1996). However, in these studies it is re-searchers who theorized the causal dimensions and…

  15. 28 CFR 51.57 - Relevant factors.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Relevant factors. 51.57 Section 51.57... factors. Among the factors the Attorney General will consider in making determinations with respect to the... language minority groups into account in making the change; and (e) The factors set forth in Village...

  16. 28 CFR 51.57 - Relevant factors.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Relevant factors. 51.57 Section 51.57... factors. Among the factors the Attorney General will consider in making determinations with respect to the... language minority groups into account in making the change; and (e) The factors set forth in Village...

  17. 14 CFR 25.619 - Special factors.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Special factors. 25.619 Section 25.619... STANDARDS: TRANSPORT CATEGORY AIRPLANES Design and Construction General § 25.619 Special factors. The factor of safety prescribed in § 25.303 must be multiplied by the highest pertinent special factor of...

  18. 24 CFR 598.305 - Designation factors.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 3 2010-04-01 2010-04-01 false Designation factors. 598.305... Designation Process § 598.305 Designation factors. In choosing among nominated urban areas eligible for... connection with the strategic plan (see § 598.215(b)); and (c) Other factors. Other factors established...

  19. 5 CFR 841.404 - Demographic factors.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Demographic factors. 841.404 Section 841... factors. (a) The Office of Personnel Management (OPM) will consider the factors listed below in determining normal cost percentages. To the extent data are available for the factor by specific category...

  20. 24 CFR 598.305 - Designation factors.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 3 2011-04-01 2010-04-01 true Designation factors. 598.305 Section... § 598.305 Designation factors. In choosing among nominated urban areas eligible for designation, the... strategic plan (see § 598.215(b)); and (c) Other factors. Other factors established by HUD, as specified...

  1. 14 CFR 23.619 - Special factors.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Special factors. 23.619 Section 23.619... Special factors. The factor of safety prescribed in § 23.303 must be multiplied by the highest pertinent special factors of safety prescribed in §§ 23.621 through 23.625 for each part of the structure...

  2. 14 CFR 23.619 - Special factors.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Special factors. 23.619 Section 23.619... Special factors. The factor of safety prescribed in § 23.303 must be multiplied by the highest pertinent special factors of safety prescribed in §§ 23.621 through 23.625 for each part of the structure...

  3. 14 CFR 25.619 - Special factors.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Special factors. 25.619 Section 25.619... STANDARDS: TRANSPORT CATEGORY AIRPLANES Design and Construction General § 25.619 Special factors. The factor of safety prescribed in § 25.303 must be multiplied by the highest pertinent special factor of...

  4. Bayesian Estimation of Categorical Dynamic Factor Models

    ERIC Educational Resources Information Center

    Zhang, Zhiyong; Nesselroade, John R.

    2007-01-01

    Dynamic factor models have been used to analyze continuous time series behavioral data. We extend 2 main dynamic factor model variations--the direct autoregressive factor score (DAFS) model and the white noise factor score (WNFS) model--to categorical DAFS and WNFS models in the framework of the underlying variable method and illustrate them with…

  5. The Arabidopsis thaliana Nuclear Factor Y Transcription Factors

    PubMed Central

    Zhao, Hang; Wu, Di; Kong, Fanying; Lin, Ke; Zhang, Haishen; Li, Gang

    2017-01-01

    Nuclear factor Y (NF-Y) is an evolutionarily conserved trimeric transcription factor complex present in nearly all eukaryotes. The heterotrimeric NF-Y complex consists of three subunits, NF-YA, NF-YB, and NF-YC, and binds to the CCAAT box in the promoter regions of its target genes to regulate their expression. Yeast and mammal genomes generally have single genes with multiple splicing isoforms that encode each NF-Y subunit. By contrast, plant genomes generally have multi-gene families encoding each subunit and these genes are differentially expressed in various tissues or stages. Therefore, different subunit combinations can lead to a wide variety of NF-Y complexes in various tissues, stages, and growth conditions, indicating the potentially diverse functions of this complex in plants. Indeed, many recent studies have proved that the NF-Y complex plays multiple essential roles in plant growth, development, and stress responses. In this review, we highlight recent progress on NF-Y in Arabidopsis thaliana, including NF-Y protein structure, heterotrimeric complex formation, and the molecular mechanism by which NF-Y regulates downstream target gene expression. We then focus on its biological functions and underlying molecular mechanisms. Finally, possible directions for future research on NF-Y are also presented. PMID:28119722

  6. Cardiac risk factors: environmental, sociodemographic, and behavioral cardiovascular risk factors.

    PubMed

    Anthony, David; George, Paul; Eaton, Charles B

    2014-06-01

    Several environmental exposures are associated with increased risk of coronary heart disease (CHD). Exposure to secondhand smoke may increase the risk by as much as 25% to 30%. Exposure to third hand smoke, residual components of tobacco smoke that remain in the environment after a cigarette is extinguished, also appears to increase risk. These residual components can remain in rooms and automobiles for up to 30 years and enter the body through the skin or via inhalation or ingestion. Exposure to particulate matter air pollution from automobile emissions, power plants, and other sources is yet another environmental risk factor for CHD, resulting in tens of thousands of deaths annually in the United States. Exposure to other environmental toxins, particularly bisphenol A and phthalates, also has been linked to CHD. There are sociodemographic risks for CHD, with numerous studies showing that lower socioeconomic status is associated with higher risk. Behavioral risk factors include poor diet, such as frequent consumption of fast food and processed meals; sleep disturbance; and psychological stress, particularly related to marital or work issues. Finally, although high alcohol consumption is associated with increased CHD risk, moderate alcohol consumption (ie, less than 1 to 2 drinks/day), particularly of wine and possibly beer, appears to reduce the risk.

  7. The Arabidopsis thaliana Nuclear Factor Y Transcription Factors.

    PubMed

    Zhao, Hang; Wu, Di; Kong, Fanying; Lin, Ke; Zhang, Haishen; Li, Gang

    2016-01-01

    Nuclear factor Y (NF-Y) is an evolutionarily conserved trimeric transcription factor complex present in nearly all eukaryotes. The heterotrimeric NF-Y complex consists of three subunits, NF-YA, NF-YB, and NF-YC, and binds to the CCAAT box in the promoter regions of its target genes to regulate their expression. Yeast and mammal genomes generally have single genes with multiple splicing isoforms that encode each NF-Y subunit. By contrast, plant genomes generally have multi-gene families encoding each subunit and these genes are differentially expressed in various tissues or stages. Therefore, different subunit combinations can lead to a wide variety of NF-Y complexes in various tissues, stages, and growth conditions, indicating the potentially diverse functions of this complex in plants. Indeed, many recent studies have proved that the NF-Y complex plays multiple essential roles in plant growth, development, and stress responses. In this review, we highlight recent progress on NF-Y in Arabidopsis thaliana, including NF-Y protein structure, heterotrimeric complex formation, and the molecular mechanism by which NF-Y regulates downstream target gene expression. We then focus on its biological functions and underlying molecular mechanisms. Finally, possible directions for future research on NF-Y are also presented.

  8. Understanding adverse events: human factors.

    PubMed Central

    Reason, J

    1995-01-01

    (1) Human rather than technical failures now represent the greatest threat to complex and potentially hazardous systems. This includes healthcare systems. (2) Managing the human risks will never be 100% effective. Human fallibility can be moderated, but it cannot be eliminated. (3) Different error types have different underlying mechanisms, occur in different parts of the organisation, and require different methods of risk management. The basic distinctions are between: Slips, lapses, trips, and fumbles (execution failures) and mistakes (planning or problem solving failures). Mistakes are divided into rule based mistakes and knowledge based mistakes. Errors (information-handling problems) and violations (motivational problems) Active versus latent failures. Active failures are committed by those in direct contact with the patient, latent failures arise in organisational and managerial spheres and their adverse effects may take a long time to become evident. (4) Safety significant errors occur at all levels of the system, not just at the sharp end. Decisions made in the upper echelons of the organisation create the conditions in the workplace that subsequently promote individual errors and violations. Latent failures are present long before an accident and are hence prime candidates for principled risk management. (5) Measures that involve sanctions and exhortations (that is, moralistic measures directed to those at the sharp end) have only very limited effectiveness, especially so in the case of highly trained professionals. (6) Human factors problems are a product of a chain of causes in which the individual psychological factors (that is, momentary inattention, forgetting, etc) are the last and least manageable links. Attentional "capture" (preoccupation or distraction) is a necessary condition for the commission of slips and lapses. Yet, its occurrence is almost impossible to predict or control effectively. The same is true of the factors associated with

  9. Psychological factors affecting oncology conditions.

    PubMed

    Grassi, Luigi; Biancosino, Bruno; Marmai, Luciana; Rossi, Elena; Sabato, Silvana

    2007-01-01

    The area of psychological factors affecting cancer has been the object of research starting from the early 1950s and consolidating from the 1970s with the development of psychooncology. A series of problems in the DSM and ICD nosological systems, such as the difficult application of the criteria for psychiatric diagnoses (i.e. major depression, adjustment disorders) and the scarce space dedicated to the rubric of psychosocial implications of medical illness (i.e. Psychological Factors Affecting a Medical Condition under 'Other Conditions That May Be a Focus of Clinical Attention' in the DSM-IV) represent a major challenge in psycho-oncology. The application of the Diagnostic Criteria for Psychosomatic Research (DCPR) has been shown to be useful in a more precise identification of several psychological domains in patients with cancer. The DCPR dimensions of health anxiety, demoralization and alexithymia have been shown to be quite frequent in cancer patient (37.7, 28.8 and 26%, respectively). The overlap between a formal DSM-IV diagnosis and the DCPR is low, with 58% of patients being categorized as non-cases on the DSM-IV having at least one DCPR syndrome. The specific quality of the DCPR in characterizing psychosocial aspects secondary to cancer is also confirmed by the fact that some dimensions of coping (e.g. Mini-Mental Adjustment to Cancer subscale hopelessness) correlate with the DCPR dimension of demoralization, while a quantitative approach on symptom assessment (e.g. stress symptoms on the Brief Symptom Inventory) is not useful in discriminating the patients with and without DCPR syndromes. More research is needed in order to understand the relationship between DCPR constructs (e.g. alexithymia) and psychosocial factors which have been shown to be significant in oncology (e.g. emotional repression and avoidance). The role of specific DCPR constructs in influencing the course of illness is also an area that should be investigated.

  10. [Conditioning factors of weight condition].

    PubMed

    San Mauro, Ismael; Megias, Ana; Bodega, Patricia; García de Angulo, Belén; Rodríguez, Paula; Grande, Graciela; Micó, Víctor; Romero, Elena; Fajardo, Diana; García, Nuria

    2015-01-01

    Introducción: Estudios epidemiológicos muestran que durante las últimas dos décadas la obesidad infantil ha aumentado convertirse en una de las principales preocupaciones de salud pública. Los hábitos dietéticos, la falta de actividad física y, el grado de obesidad empeoran con el paso de los años convirtiendo a los niños con sobrepeso en adultos con sobrepeso. Objetivo: Conocer la influencia de diversos factores modificables (hábitos alimentarios, práctica de actividad física, sedentarismo y horas de sueño), sobre el estado ponderal de un colectivo de niños en edad escolar. Método: Se realizó un estudio observacional de corte transversal retrospectivo de 129 escolares de Madrid entre 6 y 12 años con recogida de datos antropométricos (peso, talla y circunferencia de cintura), dietéticos (Kidmed), de actividad física (IPAQ adaptado), sedentarismo y horas de sueño. Resultados: El resultado más relevante fue el exceso ponderal de los niños (28,1%), aunque estos resultados no fueron significativos respecto a ninguno de los factores estudiados. Se estudió el factor de actividad física y el tiempo dedicado a actividades sedentarias en función del sexo, en ambos casos se vieron valores menores en niñas que en niños siendo estas diferencias estadísticamente significativas (p.

  11. Aetiological factors in paediatric urolithiasis.

    PubMed

    van't Hoff, William G

    2004-01-01

    The aetiology of stones in children differs from that in adults. Young children, especially boys, are prone to infective stones, although this type of calculi is decreasing in frequency over time in prosperous countries. Two monogenic causes, cystinuria and hyperoxaluria, each account for 5-15% of paediatric stones. Increased factors for stone formation in children include prematurity, neurological problems, ketogenic diet and reconstructed or augmented bladders. Hypercalciuria is commonly found in paediatric stone formers, is usually idiopathic and is only rarely associated with hypercalcaemia. All children with stones should undergo a metabolic evaluation.

  12. Prognostic factors in bunion surgery.

    PubMed

    Scranton, P E; McDermott, J E

    1995-11-01

    Between 1977 and 1992, 42 patients were seen who had 51 feet operated upon for bunions in which the surgery failed. A total of 105 procedures were done on these 51 feet until the patients either achieved satisfactory correction (N = 28) or they declined (N = 14) further surgery. An analysis of these failures and review of literature revealed 12 anatomic variations and 7 secondary factors that were seen in association with surgical failure. These findings were correlated with published criteria and our experience with various bunion procedures to advance general indications and contraindications for specific bunion procedures.

  13. Targeting Transcription Factors in Cancer

    PubMed Central

    Bhagwat, Anand S.; Vakoc, Christopher R.

    2015-01-01

    Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery. PMID:26645049

  14. Additional factors in chronic bronchitis.

    PubMed

    Cullen, K J; Elder, J; Adams, A R; Stenhouse, N S

    1970-02-14

    A review of persons with chronic bronchitis and controls without bronchitis showed several irritants around the home that aggravated cough, such as house dust, flowers and grasses, smoke, strong fumes, hair spray, insecticide, and soap powders. Most subjects with bronchitis were affected by exposure to one or more of these irritants for at least once a day for three months of the year or more. Out of 163 subjects with chronic bronchitis only six non-smokers were free of factors associated with pulmonary irritation. This evidence from non-smokers not exposed to air pollution adds further strength to the hypothesis that daily phlegm is caused by persistent inhalation of irritants.

  15. Human factors in spacecraft design.

    PubMed

    Harrison, A A; Connors, M M

    1990-01-01

    This paper describes some of the salient implications of evolving mission parameters for spacecraft design. Among the requirements for future spacecraft are new, higher standards of living, increased support of human productivity, and greater accommodation of physical and cultural variability. Design issues include volumetric allowances, architecture and layouts, closed life support systems, health maintenance systems, recreational facilities, automation, privacy, and decor. An understanding of behavioral responses to design elements is a precondition for critical design decisions. Human factors research results must be taken into account early in the course of the design process.

  16. [Environmental factors in Asperger syndrome].

    PubMed

    Abe, Takaaki; Kato, Satoshi

    2007-03-01

    This paper reviews what is currently known about the environmental factors in Asperger syndrome that is a neurodevelopmental disorder of genetic origins. Its characteristics tend to occur in families of those with the syndrome. The rate of complications during pregnancy or the neonatal period in the patients with Asperger syndrome was about the same as that in the control group. It is true that their involvement in their outer world could not influence the core social deficits very much. But it might facilitate the appearance of the second symptoms such as dissociation, anxiety, depression, persecutory delusion as well as antisocial behavior including serious criminal acts.

  17. Human factors in spacecraft design

    NASA Technical Reports Server (NTRS)

    Harrison, Albert A.; Connors, Mary M.

    1990-01-01

    This paper describes some of the salient implications of evolving mission parameters for spacecraft design. Among the requirements for future spacecraft are new, higher standards of living, increased support of human productivity, and greater accommodation of physical and cultural variability. Design issues include volumetric allowances, architecture and layouts, closed life support systems, health maintenance systems, recreational facilities, automation, privacy, and decor. An understanding of behavioral responses to design elements is a precondition for critical design decisions. Human factors research results must be taken into account early in the course of the design process.

  18. Human factors in space telepresence

    NASA Technical Reports Server (NTRS)

    Akin, D. L.; Howard, R. D.; Oliveria, J. S.

    1983-01-01

    The problems of interfacing a human with a teleoperation system, for work in space are discussed. Much of the information presented here is the result of experience gained by the M.I.T. Space Systems Laboratory during the past two years of work on the ARAMIS (Automation, Robotics, and Machine Intelligence Systems) project. Many factors impact the design of the man-machine interface for a teleoperator. The effects of each are described in turn. An annotated bibliography gives the key references that were used. No conclusions are presented as a best design, since much depends on the particular application desired, and the relevant technology is swiftly changing.

  19. Human Factors in Space Flight

    NASA Technical Reports Server (NTRS)

    Woolford, Barbara J.; Mount, Frances

    2005-01-01

    After forty years of experience with human space flight (Table 1), the current emphasis is on the design of space vehicles, habitats, and missions to ensure mission success. What lessons have we learned that will affect the design of spacecraft for future space exploration, leading up to exploring Mars? This chapter addresses this issue in four sections: Anthropometry and Biomechanics; Environmental Factors; Habitability and Architecture; and Crew Personal Sustenance. This introductory section introduces factors unique to space flight. A unique consideration for design of a habitable volume in a space vehicle is the lack of gravity during a space flight, referred to as microgravity. This affects all aspects of life, and drives special features in the habitat, equipment, tools, and procedures. The difference in gravity during a space mission requires designing for posture and motion differences. In Earth s gravity, or even with partial gravity, orientation is not a variable because the direction in which gravity acts defines up and down. In a microgravity environment the working position is arbitrary; there is no gravity cue. Orientation is defined primarily through visual cues. The orientation within a particular crew station or work area is referred to as local vertical, and should be consistent within a module to increase crew productivity. Equipment was intentionally arranged in various orientations in one module on Skylab to assess the efficiency in use of space versus the effects of inconsistent layout. The effects of that arrangement were confusion on entering the module, time spent in re-orientation, and conflicts in crew space requirements when multiple crew members were in the module. Design of a space vehicle is constrained by the three major mission drivers: mass, volume and power. Each of these factors drives the cost of a mission. Mass and volume determine the size of the launch vehicle directly; they can limit consumables such as air, water, and

  20. Environmental Risk Factors for ARDS

    PubMed Central

    Moazed, Farzad; Calfee, Carolyn S.

    2014-01-01

    The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in critically ill patients. Over the past several decades, alcohol abuse and cigarette smoke exposure have been identified as risk factors for the development of ARDS. The mechanisms underlying these relationships are complex and remain under investigation but are thought to involve pulmonary immune impairment as well as alveolar epithelial and endothelial dysfunction. This review summarizes the epidemiologic data supporting links between these exposures and ARDS susceptibility and outcomes and highlights key mechanistic investigations that provide insight into the pathways by which each exposure is linked to ARDS. PMID:25453414